Using 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), we tested the hypothesis that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are important controllers of cerebral O2 supply/consumption balance in newborn piglets during both normoxia and hypoxia. Twenty-seven 2- to 7-day-old piglets were anesthetized with alpha-chloralose and were divided into four groups: 1) normoxia (n = 7), 2) GYKI 52466 (10 mg/kg, n = 7), 3) hypoxia (n = 6), and 4) hypoxia + GYKI 52466 (n = 7). We used [14C]iodoantipyrine to measure regional cerebral blood flow (rCBF) in mL/min/100 g, and we determined O2 extraction by microspectrophotometry, calculating cerebral O2 consumption (VO2) in mL O2/min/100 g in the cortex, hypothalamus, and pons. GYKI 52466 had no effect on regional VO2 or rCBF in normoxic piglets compared with controls. Hypoxia resulted in an increase in local VO2 and rCBF in the cortex and hypothalamus compared with controls: rCBF from 50 +/- 10 to 97 +/- 16 and VO2 from 2.4 +/- 0.5 to 3.7 +/- 0.4 in the cortex, and rCBF from 41 +/- 9 to 99 +/- 17 and VO2 from 2.5 +/- 1 to 3.8 +/- 0.5 in the hypothalamus. GYKI 52466 abolished this hypoxic flow effect in both the cortex (68 +/- 14) and hypothalamus (73 +/- 12). GYKI 52466 also blocked the increased VO2 in the cortex (2.5 +/- 0.4) and hypothalamus (3.0 +/- 0.5) of the hypoxic group. These findings suggest that the AMPA receptor is an important controller of VO2 in the cortex and hypothalamus during hypoxia in this immature porcine model.