Oxidative phosphorylation system during steady-state hypoxia in the dog brain

Abstract

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.

Bioenergetic Analysis of Oxidative Metabolism Following Traumatic Brain Injury in Rats

“…Since NADH concentration in brain is normally 50 times higher than the Km for NADH (10 uM), this term in equation (2) is negligible and can be ignored (Nioka et al, 1990(Nioka et al, ,1991. Similarly, we have assumed that before injury there is no oxygen limitation and that oxygen concentration is far in excess of its Km (0.1 |iM), thereby effectively eliminating this term from the equation.…”

Regional cerebral blood flow during acute hypoxia in individuals susceptible to acute mountain sickness

“…Prior studies have shown that cerebral oxygen delivery is maintained over several hours of exposure to hypoxia in humans (Wolff 2000) and in animals (Nioka et al 1990). During 30 minutes of acute 12.5% hypoxia we observed no significant decrease in cerebral oxygen delivery to either white matter or grey matter regions, indicating that cerebral oxygen delivery is maintained during the acute-phase response to acute hypoxia as well.…”

Effects of Glucose and Pa o 2 Modulation on Cortical Intracellular Acidosis, NADH Redox State, and Infarction in the Ischemic Penumbra

“…ATP, ADP, and AMP do not change unless the PaO 2 is Ͻ25 mm Hg, whereas phosphocreatine, NADH redox state, and pH i change at Ͻ35 mm Hg. 52,55 However, the lactate and pyruvate levels begin to increase when the PaO 2 is Ͻ50 mm Hg. This would explain in part why the severely hyperglycemic/moderately hypoxic animals were markedly more acidotic than the severely hyperglycemic/normoxic animals.…”