The Coupling between Epilepsy and Cortical Spreading Depression of Leão
Main Article Content
Abstract
Objectives: The discovery of cortical spreading depression 80 years ago by Leão was intimately connected to epilepsy research. In our studies we found that monitoring of brain hemodynamics, metabolic ionic and electrical activities are very similar in the two pathophysiological events. Here we are presenting the coupling between epilepsy and cortical spreading depression while monitoring of mitochondrial nicotinamide adenine dinucleotide-NADH together with other physiological parameters in real time in vivo.
Methods: Rats and Mongolian gerbils were used in three models of induction of epilepsy, namely injection of pentylenetetrazol-metrazol, exposure of the rats to hyperbaric oxygenation in a pressure chamber and using a strain of gerbils that are developing seizures spontaneously. We monitored brain oxygen levels, mitochondrial NADH, extracellular potassium levels, Direct Current-DC steady potential and electroencephalography-EEG in the very slightly anesthetized animals.
Results: The results could be summarized as follows: 1. In almost all animal tested cortical spreading depression was developed and recorded after 1-3 minutes of seizures activity. 2. Mitochondrial NADH redox state was more oxidized during the two events. 3. The oxidation of NADH during the Cortical Spreading Depression- CSD was 3-4 times relative to the seizure’s interval. 4. The increase in extracellular potassium levels was also 3-4 times higher during the CSD event.
Significance: Under the two recorded events a clear correlation between the process of oxygen (energy) demand or consumption and oxygen (energy) supply was found. The results suggest that the accumulation of extracellular potassium during the epileptic activity is probably the trigger for the development of CSD in the 3 model used.
Keywords:
Mitochondrial NADH, Hyperbaric oxygenation, extracellular potassium, seizure prone Gerbils, Brain oxygen balance
Article Details
How to Cite
MAYEVSKY, Avraham.
The Coupling between Epilepsy and Cortical Spreading Depression of Leão.
Medical Research Archives, [S.l.], v. 11, n. 7.1, july 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4122>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i7.1.4122.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2 Ince, R., Adanir, S.S., Sevmez, F., 2021. The inventor of electroencephalography (EEG): Hans Berger (1873-1941). Childs Nerv. Syst. 37, 2723-2724..
3 Rosenblueth, A., Cannon, W.B., 1942. Cortical responses to electric stimulation. Am. J. Physiol. 135, 690-744..
4 Somjen, G.G., 2005. Aristides Leão's discovery of cortical spreading depression. J. Neurophysiol. 94, 2-4..
5 Leão, A.A.P., 1944. Pial circulation and spreading depression of activity in the cerebral cortex. J. Neurophysiol. 7, 391-396..
6 Leão, A.A.P., 1943. Spreading depression of activity in the cerebral cortex. Thesis, Harvard University, USA..
7 Leão, A.A.P., 1944. Spreading depression of activity in cerebral cortex. J. Neurophysiol. 7, 359-390..
8 Mayevsky, A., Chance, B., 1973. A new long-term method for the measurement of NADH fluorescence in intact rat brain with implanted cannula, in: Bicher, H.I., Bruley, D.F. (Eds.). Plenum Press, New York, pp. 239-244..
9 Chance, B., Oshino, N., Sugano, T., Mayevsky, A., 1973. Basic principles of tissue oxygen determination from mitochondrial signals. Oxygen Transport to Tissue, Adv. Exp. Med. Biol. 37A, 277-292..
10 Mayevsky, A., Chance, B., 2007. Oxidation-reduction states of NADH in vivo: from animals to clinical use. Mitochondrion 7, 330-339..
11 Mayevsky, A., Barbiro-Michaely, E., 2013. Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: I. Basic methodology and animal studies. J. Clin. Monit. Comp. 27, 1-34..
12 Mayevsky, A., Barbiro-Michaely, E., 2013. Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: II: Human studies. J. Clin. Monit. Comp. 27, 125-145..
13 Friedli, C.M., Sclarsky, D.S., Mayevsky, A., 1982. Multiprobe monitoring of ionic, metabolic, and electrical activities in the awake brain. Am. J. Physiol. 243, R462-469..
14 Mayevsky, A., Zarchin, N., Yoles, E., Tannenbaum, B., 1986. Oxygen supply to the brain in hypoxic and hyperoxic conditions, in: Nicolau, C. (Ed.), Advances in the Biosciences. “O2-Transport in Red Blood Cells”. Pergamon Press, pp. 119-132..
15 Mayevsky, A., 1983. Multiparameter monitoring of the awake brain under hyperbaric oxygenation. J. Appl. Physiol 54, 740-748..
16 Mayevsky, A., Shaya, B., 1980. Factors affecting the development of hyperbaric oxygen toxicity in the awake rat brain. J. Appl. Physiol. 49, 700-707..
17 Mayevsky, A., 1975. The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO. J. Neurosci. Res. 1, 131-142..
18 Mayevsky, A., 1978. The responses of an awake brain to HPO under increased CO2 concentration. Adv. Exp. Med. Biol. 92, 735-740..
19 Mayevsky, A., Chance, B., 1975. Metabolic responses of the awake cerebral cortex to anoxia hypoxia spreading depression and epileptiform activity. Brain Res. 98, 149-165..
20 Harbig, K., Chance, B., Kovach, A.G.B., Reivich, M., 1976. In vivo measurement of pyridine nucleotide fluorescence from cat brain cortex. J. Appl. Physiol. 41, 480-488..
21 Jobsis, F.F., O'Connor, M., Vitale, A., Vreman, H., 1971. Intracellular redox changes in functioning cerebral cortex. I. Metabolic effects of epileptiform activity. J. Neurophysiol. 3465, 735-749..
22 Mayevsky, A., Jamieson, D., Chance, B., 1974. Oxygen poisoning in the unanesthetized brain: correlation of the oxidation-reduction state of pyridine nucleotide with electrical activity. Brain Res. 76, 481-491..
23 Gersh, I., Wagner, C.E., 1945. Metabolic factors in oxygen poisoning. Am. J. Physiol.-Legacy Content 144, 270–277..
24 Hempel, F.G., Jobsis, F.F., LaManna, J.L., Rosenthal, M.R., Saltzman, H.A., 1977. Oxidation of cerebral cytochrome aa3 by oxygen plus carbon dioxide at hyperbaric pressures. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 43, 873-879..
25 Shilling, C.W., Adams, B.H., 1933. A Study of the Convulsive Seizures Caused by Breathing Oxygen at High Pressures. Naval Medical Bulletin 31, 112-121..
26 Bean, J.W., 1945. Effects of oxygen at increased pressure. Physiological Reviews 25, 1-147..
27 Stein, S.N., Sonnenschein, R.R., 1950. Electrical activity and oxygen tension of brain during hyperoxie convulsions. J. Aviat. Med. 21, 401-405..
28 Torbati, D., Parolla, D., Lavy, S., 1977. Changes in local brain tissue PO2 and electrocortical activity of unanesthetized rabbits under high oxygen pressure. Aviat. Space Environ. Med. 48, 247-250..
29 Bean, J.W., Lignell, J., Burgess, D.W., 1972. Cerebral O2, CO2, regional cerebral vascular control, and hyperbaric oxygenation. J Appl. Physiol. 32, 650-657..
30 Chance, B., Jamieson, D., Coles, H., 1965. Energy-linked pyridine nucleotide reduction: inhibitory effects of hyperbaric oxygen in vitro and in vivo. Nature 4981, 257-263..
31 Chance, B., Jamieson, D., Williamson, J.R., 1966. Control of the oxidation-reduction state of reduced pyridine nucleotides in vivo and in vitro by hyperbaric oxygen, Third International Conference on Hyperbaric Medicine, National Academy of Sciences, pp. 15-41..
32 Hempel, F.G., Jobsis, F.F., LaManna, J.L., Rosenthal, M.R., Saltzman, H.A., 1977. Oxidation of cerebral cytochrome aa3 by oxygen plus carbon dioxide at hyperbaric pressures. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 43, 873-879..
33 Mayevsky, A., Sclarsky, D.S., 1983. Correlation of brain NADH redox state, K+, PO2 and electrical activity during hypoxia, ischemia and spreading depression. Adv. Exp. Med. Biol. 159, 129-141..
34 Mayevsky, A., Kaplan, H., Haveri, J., Haselgrove, J., Chance, B., 1986. Three-dimensional metabolic mapping of the freeze-trapped brain: Effects of ischemia on the Mongolian gerbil. Brain Res. 367, 63-72..
35 Mayevsky, A., Rogatsky, G., 2007. Mitochondrial function in vivo evaluated by NADH fluorescence: From animal models to human studies. Am. J. Physiol. Cell Physiol. 292, C615-C640..
36 Fabricius, M., Fuhr, S., Willumsen, L., Dreier, J.P., Bhatia, R., Boutelle, M.G., Hartings, J.A., Bullock, R., Strong, A.J., Lauritzen, M., 2008. Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clin. Neurophysiol. 119, 1973-1984..
37 Koroleva, V.I., Bures, J., 1983. Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp. Brain Res. 51, 291-297..
38 Koroleva, V.I., Bures, J., 1979. Circulation of cortical spreading depression around electrically stimulated areas and epileptic foci in the neocortex of rats. Brain Res. 173, 209-215..
39 O'Connor, M.J., Herman, C.J., Rosenthal, M., Jobsis, F., 1972. Intracellular redox changes preceding onset of epileptiform activity in intact cat hippocampus. J. Neurophysiol. 35, 471-483..
40 Lewis, D.V., O'Connor, M.J., Schuette, W.H., 1974. Oxidative metabolism during recurrent seizures in the penicillin treated hippocampus. Electroencephalogr. Clin. Neurophysiol. 36, 347-356..
41 Izquierdo, I., Nasello, A.G., Marichich, E.S., 1970. Effects of potassium on rat hippocampus: the dependence of hippocampal evoked and seizure activity on extracellular potassium levels. Arch. Int. Pharmacodyn. Ther. 187, 318-328..
42 Fertziger, A.P., Ranck, J.B., Jr., 1970. Potassium accumulation in interstitial space during epileptiform seizures. Exp. Neurol. 26, 571-585..
43 Moody, W.J., Futamachi, K.J., Prince, D.A., 1974. Extracellular potassium activity during epileptogenesis. Exp. Neurol. 42, 248-263..
44 Janebova, M., 1971. Excitation of Leão's cortical spreading depression by threshold amounts of electrophoretically applied K+ ions. Physiol. Bohemoslov. 20, 447-451..
45 Marshall, J.R., Lambertsen, C.J., 1961. Interactions of increased pO2 and pCO2 effects in producing convulsions and death in mice. J. Appl. Physiol. 16, 1-7..
46 Wood, J.D., 1980. GABA and oxygen toxicity: A review. Brain Research Bulletin 5, 777–780..
47 Bean, J.W., Leatherman, N.E., 1969. Cerebral blood flow during convulsions: Alterations induced in animals by high pressure oxygen. Arch. Neurol. 20, 396-405..
48 Somjen, G.G., Rosenthal, M., Cordingley, G., LaManna, J., Lothman, E., 1976. Potassium, neuroglia, and oxidative metabolism in central gray matter. Fed. Proc. 35, 1266-1271..
49 Heinemann, U., Lux, H.D., 1975. Undershoots following stimulus-induced rises of extracellular potassium concentration in cerebral cortex of cat. Brain Res. 93, 63-76..
50 Ookawa, T., Bures, J., 1975. Extracellular potassium shifts accompanying epileptic discharge induced in chicken hyperstriatum by systemic injection of Metrazol. Brain Res. 97, 171-176..
51 Boldt, M., Harbig, K., Weidemann, G., Lubbers, D.W., 1980. A sensitive dual wavelength microspectrophotometer for the measurement of tissue fluorescence and reflectance. Pfluegers Arch. Eur. J. Physiol. 385, 167-173..
52 Kaplan, S.A., Stein, S.N., 1957. Effects of oxygen at high pressure on the transport of potassium, sodium and glutamate in guinea pig brain cortex. Am. J. Physiol. 190, 157-162..
53 Chance, B., Williams, G.R., 1955. Respiratory enzymes in oxidative phosphorylation (I- Kinetics of oxygen utilization). J. Biol. Chem. 217, 383-393..
54 Lewis, D.V., Schuette, W.H., 1975. NADH fluorescence and [K+]o changes during hippocampal electrical stimulation. J. Neurophysiol. 38, 405-417..
55 Mayevsky, A., 2023. The 80th Anniversary of Cortical Spreading Depression of Leão: A Major Component in Experimental and Clinical Neuropathology. Br. J.Healthcare Med. Res. 10, 388-408..
56 Chance, B., Barlow, C., Haselgrove, J., Nakase, Y., Quistorff, B., Matschinsky, F., Mayevsky, A., 1978. Microheterogeneities of redox states of perfused and intact organs, in: Srere, P. (Ed.), Microenvironments and Metabolic Compartmentation. Academic Press, New York, pp. 131-148.
2 Ince, R., Adanir, S.S., Sevmez, F., 2021. The inventor of electroencephalography (EEG): Hans Berger (1873-1941). Childs Nerv. Syst. 37, 2723-2724..
3 Rosenblueth, A., Cannon, W.B., 1942. Cortical responses to electric stimulation. Am. J. Physiol. 135, 690-744..
4 Somjen, G.G., 2005. Aristides Leão's discovery of cortical spreading depression. J. Neurophysiol. 94, 2-4..
5 Leão, A.A.P., 1944. Pial circulation and spreading depression of activity in the cerebral cortex. J. Neurophysiol. 7, 391-396..
6 Leão, A.A.P., 1943. Spreading depression of activity in the cerebral cortex. Thesis, Harvard University, USA..
7 Leão, A.A.P., 1944. Spreading depression of activity in cerebral cortex. J. Neurophysiol. 7, 359-390..
8 Mayevsky, A., Chance, B., 1973. A new long-term method for the measurement of NADH fluorescence in intact rat brain with implanted cannula, in: Bicher, H.I., Bruley, D.F. (Eds.). Plenum Press, New York, pp. 239-244..
9 Chance, B., Oshino, N., Sugano, T., Mayevsky, A., 1973. Basic principles of tissue oxygen determination from mitochondrial signals. Oxygen Transport to Tissue, Adv. Exp. Med. Biol. 37A, 277-292..
10 Mayevsky, A., Chance, B., 2007. Oxidation-reduction states of NADH in vivo: from animals to clinical use. Mitochondrion 7, 330-339..
11 Mayevsky, A., Barbiro-Michaely, E., 2013. Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: I. Basic methodology and animal studies. J. Clin. Monit. Comp. 27, 1-34..
12 Mayevsky, A., Barbiro-Michaely, E., 2013. Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: II: Human studies. J. Clin. Monit. Comp. 27, 125-145..
13 Friedli, C.M., Sclarsky, D.S., Mayevsky, A., 1982. Multiprobe monitoring of ionic, metabolic, and electrical activities in the awake brain. Am. J. Physiol. 243, R462-469..
14 Mayevsky, A., Zarchin, N., Yoles, E., Tannenbaum, B., 1986. Oxygen supply to the brain in hypoxic and hyperoxic conditions, in: Nicolau, C. (Ed.), Advances in the Biosciences. “O2-Transport in Red Blood Cells”. Pergamon Press, pp. 119-132..
15 Mayevsky, A., 1983. Multiparameter monitoring of the awake brain under hyperbaric oxygenation. J. Appl. Physiol 54, 740-748..
16 Mayevsky, A., Shaya, B., 1980. Factors affecting the development of hyperbaric oxygen toxicity in the awake rat brain. J. Appl. Physiol. 49, 700-707..
17 Mayevsky, A., 1975. The effect of trimethadione on brain energy metabolism and EEG activity of the conscious rat exposed to HPO. J. Neurosci. Res. 1, 131-142..
18 Mayevsky, A., 1978. The responses of an awake brain to HPO under increased CO2 concentration. Adv. Exp. Med. Biol. 92, 735-740..
19 Mayevsky, A., Chance, B., 1975. Metabolic responses of the awake cerebral cortex to anoxia hypoxia spreading depression and epileptiform activity. Brain Res. 98, 149-165..
20 Harbig, K., Chance, B., Kovach, A.G.B., Reivich, M., 1976. In vivo measurement of pyridine nucleotide fluorescence from cat brain cortex. J. Appl. Physiol. 41, 480-488..
21 Jobsis, F.F., O'Connor, M., Vitale, A., Vreman, H., 1971. Intracellular redox changes in functioning cerebral cortex. I. Metabolic effects of epileptiform activity. J. Neurophysiol. 3465, 735-749..
22 Mayevsky, A., Jamieson, D., Chance, B., 1974. Oxygen poisoning in the unanesthetized brain: correlation of the oxidation-reduction state of pyridine nucleotide with electrical activity. Brain Res. 76, 481-491..
23 Gersh, I., Wagner, C.E., 1945. Metabolic factors in oxygen poisoning. Am. J. Physiol.-Legacy Content 144, 270–277..
24 Hempel, F.G., Jobsis, F.F., LaManna, J.L., Rosenthal, M.R., Saltzman, H.A., 1977. Oxidation of cerebral cytochrome aa3 by oxygen plus carbon dioxide at hyperbaric pressures. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 43, 873-879..
25 Shilling, C.W., Adams, B.H., 1933. A Study of the Convulsive Seizures Caused by Breathing Oxygen at High Pressures. Naval Medical Bulletin 31, 112-121..
26 Bean, J.W., 1945. Effects of oxygen at increased pressure. Physiological Reviews 25, 1-147..
27 Stein, S.N., Sonnenschein, R.R., 1950. Electrical activity and oxygen tension of brain during hyperoxie convulsions. J. Aviat. Med. 21, 401-405..
28 Torbati, D., Parolla, D., Lavy, S., 1977. Changes in local brain tissue PO2 and electrocortical activity of unanesthetized rabbits under high oxygen pressure. Aviat. Space Environ. Med. 48, 247-250..
29 Bean, J.W., Lignell, J., Burgess, D.W., 1972. Cerebral O2, CO2, regional cerebral vascular control, and hyperbaric oxygenation. J Appl. Physiol. 32, 650-657..
30 Chance, B., Jamieson, D., Coles, H., 1965. Energy-linked pyridine nucleotide reduction: inhibitory effects of hyperbaric oxygen in vitro and in vivo. Nature 4981, 257-263..
31 Chance, B., Jamieson, D., Williamson, J.R., 1966. Control of the oxidation-reduction state of reduced pyridine nucleotides in vivo and in vitro by hyperbaric oxygen, Third International Conference on Hyperbaric Medicine, National Academy of Sciences, pp. 15-41..
32 Hempel, F.G., Jobsis, F.F., LaManna, J.L., Rosenthal, M.R., Saltzman, H.A., 1977. Oxidation of cerebral cytochrome aa3 by oxygen plus carbon dioxide at hyperbaric pressures. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 43, 873-879..
33 Mayevsky, A., Sclarsky, D.S., 1983. Correlation of brain NADH redox state, K+, PO2 and electrical activity during hypoxia, ischemia and spreading depression. Adv. Exp. Med. Biol. 159, 129-141..
34 Mayevsky, A., Kaplan, H., Haveri, J., Haselgrove, J., Chance, B., 1986. Three-dimensional metabolic mapping of the freeze-trapped brain: Effects of ischemia on the Mongolian gerbil. Brain Res. 367, 63-72..
35 Mayevsky, A., Rogatsky, G., 2007. Mitochondrial function in vivo evaluated by NADH fluorescence: From animal models to human studies. Am. J. Physiol. Cell Physiol. 292, C615-C640..
36 Fabricius, M., Fuhr, S., Willumsen, L., Dreier, J.P., Bhatia, R., Boutelle, M.G., Hartings, J.A., Bullock, R., Strong, A.J., Lauritzen, M., 2008. Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clin. Neurophysiol. 119, 1973-1984..
37 Koroleva, V.I., Bures, J., 1983. Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp. Brain Res. 51, 291-297..
38 Koroleva, V.I., Bures, J., 1979. Circulation of cortical spreading depression around electrically stimulated areas and epileptic foci in the neocortex of rats. Brain Res. 173, 209-215..
39 O'Connor, M.J., Herman, C.J., Rosenthal, M., Jobsis, F., 1972. Intracellular redox changes preceding onset of epileptiform activity in intact cat hippocampus. J. Neurophysiol. 35, 471-483..
40 Lewis, D.V., O'Connor, M.J., Schuette, W.H., 1974. Oxidative metabolism during recurrent seizures in the penicillin treated hippocampus. Electroencephalogr. Clin. Neurophysiol. 36, 347-356..
41 Izquierdo, I., Nasello, A.G., Marichich, E.S., 1970. Effects of potassium on rat hippocampus: the dependence of hippocampal evoked and seizure activity on extracellular potassium levels. Arch. Int. Pharmacodyn. Ther. 187, 318-328..
42 Fertziger, A.P., Ranck, J.B., Jr., 1970. Potassium accumulation in interstitial space during epileptiform seizures. Exp. Neurol. 26, 571-585..
43 Moody, W.J., Futamachi, K.J., Prince, D.A., 1974. Extracellular potassium activity during epileptogenesis. Exp. Neurol. 42, 248-263..
44 Janebova, M., 1971. Excitation of Leão's cortical spreading depression by threshold amounts of electrophoretically applied K+ ions. Physiol. Bohemoslov. 20, 447-451..
45 Marshall, J.R., Lambertsen, C.J., 1961. Interactions of increased pO2 and pCO2 effects in producing convulsions and death in mice. J. Appl. Physiol. 16, 1-7..
46 Wood, J.D., 1980. GABA and oxygen toxicity: A review. Brain Research Bulletin 5, 777–780..
47 Bean, J.W., Leatherman, N.E., 1969. Cerebral blood flow during convulsions: Alterations induced in animals by high pressure oxygen. Arch. Neurol. 20, 396-405..
48 Somjen, G.G., Rosenthal, M., Cordingley, G., LaManna, J., Lothman, E., 1976. Potassium, neuroglia, and oxidative metabolism in central gray matter. Fed. Proc. 35, 1266-1271..
49 Heinemann, U., Lux, H.D., 1975. Undershoots following stimulus-induced rises of extracellular potassium concentration in cerebral cortex of cat. Brain Res. 93, 63-76..
50 Ookawa, T., Bures, J., 1975. Extracellular potassium shifts accompanying epileptic discharge induced in chicken hyperstriatum by systemic injection of Metrazol. Brain Res. 97, 171-176..
51 Boldt, M., Harbig, K., Weidemann, G., Lubbers, D.W., 1980. A sensitive dual wavelength microspectrophotometer for the measurement of tissue fluorescence and reflectance. Pfluegers Arch. Eur. J. Physiol. 385, 167-173..
52 Kaplan, S.A., Stein, S.N., 1957. Effects of oxygen at high pressure on the transport of potassium, sodium and glutamate in guinea pig brain cortex. Am. J. Physiol. 190, 157-162..
53 Chance, B., Williams, G.R., 1955. Respiratory enzymes in oxidative phosphorylation (I- Kinetics of oxygen utilization). J. Biol. Chem. 217, 383-393..
54 Lewis, D.V., Schuette, W.H., 1975. NADH fluorescence and [K+]o changes during hippocampal electrical stimulation. J. Neurophysiol. 38, 405-417..
55 Mayevsky, A., 2023. The 80th Anniversary of Cortical Spreading Depression of Leão: A Major Component in Experimental and Clinical Neuropathology. Br. J.Healthcare Med. Res. 10, 388-408..
56 Chance, B., Barlow, C., Haselgrove, J., Nakase, Y., Quistorff, B., Matschinsky, F., Mayevsky, A., 1978. Microheterogeneities of redox states of perfused and intact organs, in: Srere, P. (Ed.), Microenvironments and Metabolic Compartmentation. Academic Press, New York, pp. 131-148.