Cerebral ischemia can cause intracellular pH (pHi) to decrease by approximately 0.6 to 1.5 or more units, and intracellular PCO2 to increase to approximately 200 mmHg. In vitro studies suggest that intracellular acidosis augments the injury produced by cerebral ischemia. During adequate oxygenation in vivo, however, hypercapnic acidosis from PaCO2 = 500 mmHg, which lowers pHi by 0.65 units, is not injurious per se. Rather than be a cause of hypoxic/ischemic injury, decrements in pHi could be manifestation. The general aim of our rabbit and rat experiments, to test the hypothesis that intracellular acidosis is not a determinant of in vivo hypoxic or ischemic brain injury, will be pursued by exploring aspects of the relationship between hypercapnia, acidosis, hypoxia, and cerebral injury: 1. If an adequate supply of oxygen is available, is there a level of intracellular acidosis that injures the brain? A hyperbaric chamber will be used to achieve PCO2 tensions > 1 atm, while maintaining adequate PO2 tensions. Nuclear magnetic resonance (NMR) spectroscopy will be used in vivo to determine the lowest pHi tolerated by the oxygenated, hypercapnic brain. Injury will be quantified using neurochemical and neurohistological methods, and neurobehavioral outcome studies. 2. Is hypoxic brain injury increased by respiratory acidosis? Cerebral oxygen supply and demand will be assessed from simultaneous measurements of NADH fluorescence, EEG monitoring, and in vivo NMR spectroscopy. """"""""Critical oxygen levels"""""""" will be determined for pHi values of 6.9, 6.4, and 6.0. 3. Do anesthetics alter """"""""critical oxygen levels"""""""" in the brain during hypercapnic acidosis? The anesthetic effect on """"""""critical oxygen levels"""""""" will be examined by repeating the studies for issue #2 during anesthesia with halothane, isoflurane, and thiopental. 4. Does the CBF increase during hypercapnia (and its associated acidosis) protect the intracellular energy state? The effects of CBF will be examined by comparing hypercapnia-induced metabolic changes and injury at two CBF levels, one approximately 20% of the other due to indomethacin administration, each having the same PaCO2. The long term objectives of our research are: 1) to define the implications of decreased pHi for metabolic and functional brain integrity, with and without the presence of anesthetics; and, 2) to explore the interaction in brain tissue between decreases in pHi and decreases in oxygen availability, with and without general anesthetics. New in vivo technologies that can monitor intracellular responses, such as NMR spectroscopy and NADH fluorescence, will be applied in efforts to define adequate perfusion, tissue viability, and margins of safety for circumstances where such assessments are impossible with blood flow measurement and standard physiological monitoring.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034767-06
Application #
3286307
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-07-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Liu, Jia; Segal, Mark R; Kelly, Mark J S et al. (2013) 13C NMR metabolomic evaluation of immediate and delayed mild hypothermia in cerebrocortical slices after oxygen-glucose deprivation. Anesthesiology 119:1120-36
Liu, Jia; Litt, Lawrence; Segal, Mark R et al. (2011) Metabolomics of oxidative stress in recent studies of endogenous and exogenously administered intermediate metabolites. Int J Mol Sci 12:6469-501
Liu, Jia; Litt, Lawrence; Segal, Mark R et al. (2011) Outcome-related metabolomic patterns from 1H/31P NMR after mild hypothermia treatments of oxygen-glucose deprivation in a neonatal brain slice model of asphyxia. J Cereb Blood Flow Metab 31:547-59
Liu, J; Segal, M; Yoo, S et al. (2009) Antioxidant effect of ethyl pyruvate in respiring neonatal cerebrocortical slices after H(2)O(2) stress. Neurochem Int 54:106-10
Liu, Jia; Hirai, Kiyoshi; Litt, Lawrence (2008) Fructose-1,6-bisphosphate does not preserve ATP in hypoxic-ischemic neonatal cerebrocortical slices. Brain Res 1238:230-8
Zeng, Jianying; Yang, Guo-Yuan; Ying, Weihai et al. (2007) Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices. J Cereb Blood Flow Metab 27:304-15
Zeng, Jianying; Hirai, Kiyoshi; Yang, Guo-Yuan et al. (2004) Using 31P NMR spectroscopy at 14.1 Tesla to investigate PARP-1 associated energy failure and metabolic rescue in cerebrocortical slices. J Bioenerg Biomembr 36:415-9
Hirai, K; Hayashi, T; Chan, P H et al. (2003) Akt phosphorylation and cell survival after hypoxia-induced cytochrome c release in superfused respiring neonatal rat cerebrocortical slices. Acta Neurochir Suppl 86:227-30
Litt, L; Hirai, K; Basus, V J et al. (2003) NTP and PCr responses to hypoxia by hypothermic and normothermic respiring, superfused, neonatal rat cerebrocortical slices: an NMR spectroscopy study at 14.1 Tesla. Acta Neurochir Suppl 86:71-4
Litt, Lawrence; Hirai, Kiyoshi; Basus, Vladimir J et al. (2003) Temperature control of respiring rat brain slices during high field NMR spectroscopy. Brain Res Brain Res Protoc 10:191-8

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