Oxidative phosphorylation system during steady-state hypoxia in the dog brain.
The relationship between biochemical and physiological responses and tissue O2 during hypoxia was investigated in vivo in the dog brain by 31P nuclear magnetic resonance (NMR) spectroscopy. Our findings demonstrate how ATP synthesis in the brain can be maintained during hypoxia because of compensatory changes in NADH, ADP, and Pi. Eleven beagle dogs were anesthetized and mechanically ventilated, and a steady-state graded hypoxia was induced by decreasing the fraction of inspired O2 (FIO2) stepwise at 20-min intervals. Biochemical metabolites were measured using 31P-NMR and fluorescence spectroscopy. When sagittal sinus O2 partial pressure (PVO2) had decreased to 15 Torr, NADH increased by 30%, Pi increased by 50%, and phosphocreatine (PCr) decreased by 20%. In contrast, ATP remained constant. There was a 10% increase in ADP in dogs that maintained a steady temperature, but ADP decreased by as much as 30% in dogs in which body temperature decreased with the falling PVO2. PCr/Pi was logarithmically related to the phosphorylation potential during steady-state hypoxia. Compensation for the O2 lack is attributed to increases in ADP, Pi, and NADH as a result of the reciprocal relationship of the Michaelis-Menten equation. If the Michaelis-Menten constants (Km) of ADP, Pi, and O2 are the same as determined in vitro in mitochondria, the minimum brain cytosolic O2 capable of maintaining a steady-state ATP is near its Km (0.1 Torr) at a PVO2 of 7.5 Torr. At this critical O2 level, PCr/Pi is 0.9, intracellular pH is 6.75, phosphorylation potential is 38.5 mM-1, and the calculated maximum velocity of ATP formation by oxidative phosphorylation is 55% of normal.
Nioka
S
S
Department of Biochemistry/Biophysics, University of Pennsylvania, Philadelphia 19104.
Smith
D S
DS
Chance
B
B
Subramanian
H V
HV
Butler
S
S
Katzenberg
M
M
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004285:Dogs; D004734:Energy Metabolism; D006863:Hydrogen-Ion Concentration; D002534:Hypoxia, Brain / Q000378:metabolism*; D007700:Kinetics; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism
D010710:Phosphates; D010725:Phosphocreatine; D009243:NAD; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate