Factors limiting regeneration of ATP following temporary ischemia in cat brain.

Abstract

SUMMARY Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window. Postischemic perfusion, as indicated by transit time, was initially higher than control, but declined to subnormal levels by 60 minutes. NADH fluorescence transients, induced by brief anoxia, also decreased steadily during recirculation, indicating a failure of oxidation-reduction capability. The disappearance of anoxic-NADH transients usually preceded the decline of flow, suggesting that 0 2 delivery was not the factor limiting redox reactions. Furthermore, tissue levels of NADH, which were nearly normal after 2-4 hours of recirculation, did not indicate tissue hypoxia. In spite of normalization of NADH, resynthesis of high energy phosphates was severely impaired. The degree of ATP recovery varied widely in different cortical regions; however, there were two general groups of ATP values -one at 5% and the other at 70% of control levels. In the energy-depleted areas, NADH levels were normal, but the total pool of NAD (NADH + NAD + ) and the tissue content of K + were 43% lower than control. In contrast, the NAD pool and K + content were only slightly diminished in the regions with greater ATP restitution. The results suggest that postischemic resynthesis of ATP may be limited not by inadequate delivery of 0 2 , but rather by defective production of NADH.

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

“…The decline in NADH is corroborated by a previous study conducted in vivo, which showed a 43% decrease in the total pool of NAD (NADH+NAD + ) in ATP depleted areas of cortex compared to control following 30 min of ischemia and reperfusion. In areas of the cortex in which restoration of ATP was more complete, the NAD pool was only slightly decreased (Welsh et al, 1982). The present results, however, are in contrast to another in vivo study in which the maximal levels of NAD and cytochrome a,a 3 reduction did not differ when measured either prior to cerebral anoxia or during NADH hyperoxidation .…”

“…Recordings made in intact brains as well as in brain slices following either transient ischemic or hypoxic episodes revealed a decrease of NADH fluorescence and cytochrome a,a 3 reflectance significantly below control levels, which has been interpreted as hyperoxidation of intra-mitochondrial oxidative enzymes Duckrow et al, 1981;Feng et al, 1998;Paschen et al, 1985;Perez-Pinzon et al, 1998a, 1997a, 1998bPulsinelli et al, 1982;Rosenthal et al, 1995Rosenthal et al, , 1997Siesjo, 1981;Tanaka et al, 1986;Welsh et al, 1991;Welsh et al, 1982). The alternative explanation of a depletion of the electron carrier pool has been rejected by other authors .…”

Carbohydrate and Energy Metabolism during the Evolution of Hypoxic-Ischemic Brain Damage in the Immature Rat

“…Unfor tunately, technical difficulties precluded our ability to measure tissue pyruvate concentrations during and following hypoxia-ischemia, but in other stud ies levels of this metabolite increased dramatically in the immediate recovery period following perina tal hypoxia or cerebral ischemia (Vannucci and Duffy, 1976;Vannucci et al, 1980). Taken together, the data suggest that glycolytic flux is inhibited upon reoxygenation of the tissue, possibly as a re sult of the prior accumulation of reducing equiva lents (NADH) or of the preferential consumption of lactate via the oxidative pathway (Pasteur effect) (Vannucci and Duffy, 1976;Vannucci et al, 1980;Welsh et al, 1982a). However, these explanations cannot account for the curtailment of glucose utili zation, and presumably glycolytic flux, in the ipsi lateral cerebral hemisphere at 24 h of recovery, a time when the tissue should be well oxygenated (low NADH/NAD + ratio) and lactate concentra tions were at or below control levels (see Fig.…”

NMR Spectroscopic Investigation of the Recovery of Energy and Acid—Base Homeostasis in the Cat Brain after Prolonged Ischemia

“…If the ATP value of the cat brain is assumed to be 2.2 J.Lmollg wet weight (Welsh et al, 1982) and if the presence of lesser amounts of purine nucleotides that may contribute to the NTP [3 signal are ne glected, then the CrP and Pi concentrations within the brain volume sampled by the surface coil are near 4.9 and 0.9 J.Lmol/g wet weight, respectively. Intracellular pH (pHJ was determined to be 7.07 ± 0.06 (n = 7) in fully relaxed spectra and 7.06 ± 0.05 (n = 6) under partially saturated pulsing con ditions; these were not found to be significantly dif ferent.…”