Hypoxia/Ischemia and the pH Paradox

  • Joseph C. LaManna
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 388)


Hydrogen ions play an important role in cellular processes. There are intimate links between energy metabolism and the control of cell and tissue acid/base balance. Control of this balance is threatened or lost during severe hypoxia or ischemia. Re-establishment of pH balance must occur before the tissue can be considered to have returned to normal operating conditions. Because hydrogen ions influence so many reactions, the timing of renormalization can be crucial to the entire recovery process. Indeed, in many active tissues, too fast reversal of acidosis during recovery from severe hypoxia or ischemia appears to be detrimental to the overall recovery of homeostasis. That a tissue could restore function more rapidly if mild acidosis were maintained during the immediate post-stress recovery time has been referred to as the “pH paradox” (Currin et al., 1991), in analogy with the so-called “calcium paradox” that has been discussed primarily in the cardiovascular literature. In this paper we will review the changes that occur in pHi during hypoxia and ischemia in rat brain. We will explore the interrelationships of protons with metabolism, and we will propose a scheme for the interaction of protons in brain function. Finally, we will attempt to reach a conclusion concerning the applicability of the concept of pH paradox in brain.


Severe Hypoxia Functional Capillary Density Calcium Paradox Lactic Acid Accumulation Anoxic Depolarization 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Assaf, H.M., Ricci, A.J., Whittingham, T.S., LaManna, J.C, Ratcheson, R.A., and Lust, W.D., 1990, Lactate compartmentation in hippocampal slices: Evidence for a transporter, Met. Br. Dis., 5: 143–154.CrossRefGoogle Scholar
  2. Beños, D.J. and Sapirstein, VS., 1983, Characteristics of an amiloride-sensitive sodium entry pathway in cultured rodent glial and neuroblastoma cells, J. Cell. Physiol., 116: 213–220.PubMedCrossRefGoogle Scholar
  3. Bing, O.H.L., Brooks, W.W., and Messer, J.V., 1973, Heart muscle viability following hypoxia: Protective effect of acidosis, Science, 180: 1297–1298.PubMedCrossRefGoogle Scholar
  4. Blomqvist, P., Mabe, H., and Siesjö, B.K., 1982, Transient ischemia leads to intracellular alkalosis in the brain, Acta Physiol. Scand., 116: 103–104.CrossRefGoogle Scholar
  5. Bond, J.M., Chacon, E., Herman, B., and Lemasters, J.J., 1993, Intracellular pH and Ca2+ homeostasis in the pH paradox of reperfusion injury to neonatal rat cardiac myocytes, Am. J. Physiol., 265: C129–C137.PubMedGoogle Scholar
  6. Boris-Möller, F., Drakenberg, T., Ehuden, K., Forsén, S., and Siesjö, B.K., 1988, Evidence against major compartmentalization of H+ in ischemic rat brain tissue, Neurosci. Lett., 85: 113–118.PubMedCrossRefGoogle Scholar
  7. Borowsky, I.W. and Collins, R.C., 1989, Metabolic anatomy of brain: A comparison of regional capillary density, glucose metabolism, and enzyme activities, J. Comp. Neurol, 288: 401–413.PubMedCrossRefGoogle Scholar
  8. Bourke, R.S., Kimelberg, H.K., Dazé, M., and Church, G., 1983, Swelling and ion uptake in cat cerebrocortical slices: Control by neurotransmitters and ion transport mechanisms, Neurochem. Res., 8: 5–24.PubMedCrossRefGoogle Scholar
  9. Busa, W.B. and Nuccitelli, R., 1984, Metabolic regulation via intracellular pH, Am. J. Physiol, 246: R409–R438.PubMedGoogle Scholar
  10. Chesler, M., 1990, The regulation and modulation of pH in the nervous system, Prog. Neurobiol, 34: 401–427.Google Scholar
  11. Chopp, M., Welch, K.M.A., Tidwell, CD., and Helpern, J.A., 1988, Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia in cats, Stroke, 19: 1383–1387.PubMedCrossRefGoogle Scholar
  12. Chopp, M., Chen, H., Vande Linde, A.M.Q., Brown, E., and Welch, K.M.A., 1990, Time course of postischemic intracellular alkalosis reflects the duration of ischemia, J. Cereb. Blood Flow Metab., 10: 860–865.PubMedCrossRefGoogle Scholar
  13. Cohen, Y., Chang, L.-H., Litt, L., Kim, F., Severinghaus, J.W., Weinstein, RR., Davis, R.L., Germano, I., and James, T.L., 1990, Stability of brain intracellular lactate and 3^-metabolite levels at reduced intracellular pH during prolonged hypercapnia in rats, J. Cereb. Blood Flow Metab., 10: 277–284.PubMedCrossRefGoogle Scholar
  14. Combs, D.J., Dempsey, R.J., Maley, M., Donaldson, D., and Smith, C, 1990, Relationship between plasma glucose, brain lactate, and intracellular pH during cerebral ischemia in gerbils, Stroke, 21: 936–942.PubMedCrossRefGoogle Scholar
  15. Crowell, J.W. and Kaufmann, B.N., 1961, Changes in tissue pH after circulatory arrest, Am. J. Physiol, 200: 743–745.PubMedGoogle Scholar
  16. Currin, R.T., Gores, G.J., Thurman, R.G., and Lemasters, J.J., 1991, Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox, FASEB J., 5: 207–210.PubMedGoogle Scholar
  17. Davies, N.W., Standen, N.B., and Stanfield, P.R., 1992, The effect of intracellular pH on ATP-dependent potassium channels of frog skeletal muscles, J. Physiol (Lond.), 445: 549–568.Google Scholar
  18. Dennis, S.C, Gevers, W, and Opie, L.H., 1991, Protons in ischemia: Where do they come from; where do they go to?, J. Mol. Cell. Cardiol, 23: 1077–1086.PubMedCrossRefGoogle Scholar
  19. Dringen, R., Gebhardt, R., and Hamprecht, B., 1993, Glycogen in astrocytes: possible function as lactate supply for neighboring cells, Br. Res., 623: 208–214.CrossRefGoogle Scholar
  20. Ennis, S.R., Keep, R.F., Schielke, G.P., and Betz, A.L., 1990, Decrease in perfusion of cerebral capillaries during incomplete ischemia and reperfusion, J. Cereb. Blood Flow Metab., 10: 213–220.PubMedCrossRefGoogle Scholar
  21. Español, M.T., Litt, L., Yang, G.-Y., Chang, L.-H., Chan, P.H., James, T.L., and Weinstein, P.R., 1992, Tolerance of low intracellular pH during hypercapnia by rat cortical brain slices: A 31P/1H NMR study, J. Neurochem., 59: 1820–1828.PubMedCrossRefGoogle Scholar
  22. Ferimer, H.N., Kutina, K.L., and LaManna, J.C, 1995, Delayed normalization of brain intracellular pH by methyl isobutyl amiloride after cardiac arrest in rats, Crit. Care Med., (in press):.Google Scholar
  23. Fox, P.T., Raichle, M.E., Mintun, M.A., and Dence, C, 1988, Nonoxidative glucose consumption during focal physiologic neural activity, Science, 241: 462–464.PubMedCrossRefGoogle Scholar
  24. Giffard, R.G., Monyer, H., Christine, C.W., and Choi, D.W., 1990, Acidosis reduces NMDAreceptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures, Br. Res., 506: 339–342.CrossRefGoogle Scholar
  25. Gjedde, A., Kuwabara, H., and Hakim, A.M., 1990, Reduction of functional capillary density in human brain after stroke, J. Cereb. Blood Flow Metab., 10: 317–326.PubMedCrossRefGoogle Scholar
  26. Goldman, S.A., Pulsinelli, W.A., Clarke, W.Y., Kraig, R.P., and Plum, F., 1989, The effects of extracellular acidosis on neurons and glia in vitro, J. Cereb. Blood Flow Metab., 9: 471–477.PubMedCrossRefGoogle Scholar
  27. Griffith, J.K., Cordisco, B.R., Lin, C.-W., and LaManna, J.C., 1992, Distribution of intracellular pH in the rat brain cortex after global ischemia as measured by color film histophotometry of neutral red, Br. Res., 573: 1–7.CrossRefGoogle Scholar
  28. Gyulai, L., Schnall, M., McLaughlin, A.C., Leigh, J.S.J., and Chance, B., 1987, Simultaneous 31P- and ’H-nuclear magnetic resonance studies of hypoxia and ischemia in the cat brain, J. Cereb. Blood Flow Metab., 7: 543–551.PubMedCrossRefGoogle Scholar
  29. Hansen, A.J., 1985, Effect of anoxia on ion distribution in the brain, Physiol. Rev., 65: 101–148.PubMedGoogle Scholar
  30. Harris, R.J. and Symon, L., 1984, Extracellular pH, potassium, and calcium activities in progressive ischemia of rat cortex, J. Cereb. Blood Flow Metab., 4: 178–186.PubMedCrossRefGoogle Scholar
  31. Harrison, D.C., Lemasters, J.J., and Herman, B., 1991, A pH-dependent phospholipase A2 contributes to loss of plasma membrane integrity during chemical hypoxia in rat hepatocytes, Biochem. Biophys. Res. Comm., 174: 654–659.PubMedCrossRefGoogle Scholar
  32. Hochachka, P.W. and Mommsen, T.P., 1983, Protons and anaerobiosis, Science, 219: 1391–1397.PubMedCrossRefGoogle Scholar
  33. Hoffman, T.L., LaManna, J.C., Pundik, S., Selman, W.R., Whittingham, T.S., Ratcheson, R.A., and Lust, W.D., 1995, Early reversal of acidosis is a first step to metabolic recovery following ischemia, J. Neurosurg., (in press):.Google Scholar
  34. Hossmann, K.-A., 1982, Treatment of experimental cerebral ischemia, J. Cereb. Blood Flow Metab., 2: 275–297.PubMedCrossRefGoogle Scholar
  35. Hum, P.D., Koehler, R.C., Norris, S.E., Blizzard, K.K., and Traystman, R.J., 1991, Dependence of cerebral energy phosphate and evoked potential recovery on end-ischemic pH, Am. J. Physiol., 260: H532–H541.Google Scholar
  36. Jakubovicz, D.E., Grinstein, S., and Klip, A., 1987, Cell swelling following recovery from acidification in C6 glioma cells: an in vitro model of postischemic brain edema, Br. Res., 435: 138–146.CrossRefGoogle Scholar
  37. Javaheri, S., Weyne, J., and Demeester, G., 1983, Changes in the brain surface pH and cisternal cerebrospinal fluid acid-base variables in respiratory arrest, Resp. Physiol., 51: 31–43.CrossRefGoogle Scholar
  38. Kaku, D.A., Giffard, R.G., and Choi, D.W., 1993, Neuroprotective effects of glutamate antagonists and extracellular acidity, Science, 260: 1516–1518.PubMedCrossRefGoogle Scholar
  39. Kalaria, R.N., Kroon, S.N., and LaManna, J.C., 1991, Identification and characterization of the Na+/H+ antiporter of cerebral micro vessels and the choroid plexus, J. Cereb. Blood Flow Metab., 1 l(suppl): S865(Abstract).Google Scholar
  40. Katsura, K., Asplund, B., Ekholm, A., and Siesjö, B.K., 1992, Extra- and intracellular pH in the brain during ischaemia, related to tissue lactate content in normo- and hypercapnic rats, Eur. J. Neurosci., 4: 166–176.PubMedCrossRefGoogle Scholar
  41. Keung, E.C. and Li, Q., 1991, Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes,/Clin. Invest., 88: 1772–1777.CrossRefGoogle Scholar
  42. Kimelberg, H.K., Biddlecome, S., and Bourke, R.S., 1979, SITS-inhibitable C1- transport and Na+-dependent H+ production in primary astroglial cultures, Br. Res., 173: 111–124.Google Scholar
  43. Kimelberg, H.K. and Frangakis, M.V., 1985, Furosemide- and bumetanide-sensitive ion transport and volume control in primary astrocyte cultures from rat brain, Br. Res., 361: 125–134.CrossRefGoogle Scholar
  44. Kraig, R.P., Ferreira-Filho, C.S., and Nicholson, C, 1983, Alkaline and acid transients in cerebellar microenvironment, J. Neurophysiol, 49: 831–850.Google Scholar
  45. Kraig, R.P. and Chesler, M., 1990, Astrocytic acidosis in hyperglycemic and complete ischemia, J. Cereb. Blood Flow Metab., 10: 104–114.PubMedCrossRefGoogle Scholar
  46. LaManna, J.C., Assaf, H., Sick, T.J., and Whittingham, T.S., 1987, Amiloride reversal of alkaline intracellular pH in hippocampal slices, Soc. Neurosci. Abstr., 13: 126(Abstract).Google Scholar
  47. LaManna, J.C., Crumrine, R.C., and Jackson, D.L., 1988, No correlation between cerebral blood flow and neurologic recovery after reversible total cerebral ischemia in the dog, Exptl Neurol, 101: 234–247.CrossRefGoogle Scholar
  48. LaManna, J.C., Griffith, J.K., Cordisco, B.R., Lin, C.-W, and Lust, WD., 1992a, Intracellular pH in rat brain in vivo and in brain slices, Can. J. Physiol. Pharmacol, 70: S269–S277.CrossRefGoogle Scholar
  49. LaManna, J.C., Vendel, L.M., and Farrell, R.M., 1992b, Brain adaptation to chronic hypobaric hypoxia in rats, J. Appi Physiol, 72: 2238–2243.Google Scholar
  50. Lauro, K. and LaManna, J.C., 1994, Cerebral oxygen and metabolic consumption model of the compensatory adaptations in chronic hypobaric hypoxia in the rat, FASEB J., 8: A 1047(Abstract).Google Scholar
  51. Mabe, H, Blomqvist, P., and Siesjö, B.K., 1983, Intracellular pH in the brain following transient ischemia, J. Cereb. Blood Flow Metab., 3: 109–114.PubMedCrossRefGoogle Scholar
  52. Maruki, Y, Koehler, R.C., Eleff, S.M., and Traystman, R.J., 1993, Intracellular pH during reperfusion influences evoked potential recovery after complete cerebral ischemia, Stroke, 24: 697–704.PubMedCrossRefGoogle Scholar
  53. Meng, H.-R, Maddaford, T.G., and Pierce, G.N., 1993, Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function, Am. J. Physiol, 264: H1831–H1835.PubMedGoogle Scholar
  54. Meng, H.-P. and Pierce, G.N., 1990, Protective effects of 5-(AW-dimethyl)amiloride on ischemia-reperfusion injury in hearts, Am. J. Physiol, 258: H1615–H1619.PubMedGoogle Scholar
  55. Michenfelder, J.D. and Milde, J.H., 1990, Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs, J. Cereb. Blood Flow Metab., 10: 71–76.PubMedCrossRefGoogle Scholar
  56. Mies, G., Paschen, W., and Hossmann, K.-A., 1990, Cerebral blood flow, glucose utilization, regional glucose, and ATP content during the maturation period of delayed ischemic injury in gerbil brain, J. Cereb. Blood Flow Metab., 10: 638–645.PubMedCrossRefGoogle Scholar
  57. Moffat, M.P. and Karmazyn, M., 1993, Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts, J. Mol. Cell. Cardiol, 25: 959–971.PubMedCrossRefGoogle Scholar
  58. Moolenaar, W.H., 1986, Effects of growth factors on intracellular pH regulation, Ann. Rev. Physiol, 48: 363–376.CrossRefGoogle Scholar
  59. Mutch, W.A.C, and Hansen, A.J., 1984, Extracellular pH changes during spreading depression and cerebral ischemia: Mechanisms of brain pH regulation, J. Cereb. Blood Flow Metab., 4: 17–27.PubMedCrossRefGoogle Scholar
  60. Nemoto, E.M. and Frinak, S., 1981, Brain tissue pH after global brain ischemia and barbiturate loading in rats, Stroke, 12: 77–82.PubMedCrossRefGoogle Scholar
  61. Nishijima, M.K., Koehler, R.C., Hum, P.D., Eleff, S.M., Norris, S., Jacobus, W.E., and @REFAUSTY = Traystman, R.J., 1989, Postischemic recovery rate of cerebral ATP, phosphocreatine, pH and evoked potentials, Am. J. Physiol, 257: H1860–H1870.PubMedGoogle Scholar
  62. Paschen, W, Djuricic, B., Mies, G., Schmidt-Kastner, R., and Linn, F, 1987, Lactate and pH in the brain: Association and dissociation in different pathophysiological states, J. Neurochem., 48: 154–159.PubMedCrossRefGoogle Scholar
  63. Petito, C.K., Kraig, R.R, and Pulsinelli, W.A., 1987, Light and electron microscopic evaluation of hydrogen ion-induced brain necrosis, J. Cereb. Blood Flow Metab., 7: 625–632.PubMedCrossRefGoogle Scholar
  64. Plum, F, 1983, What causes infarction in ischemic brain?, Neurol, 33: 222–233.Google Scholar
  65. Sack, S., Mohiri, M., Schwarz, E.R., Arras, M., Schaper, J., Ballagi-Pordány, G., Scholz, @REFAUSTY = W, Lang, HJ., Schölkens, B.A., and Schaper, W., 1994, Effects of a new Na+/H+ antiporter inhibitor on postischemic reperfusion in pig heart, J. Cardiovasc. Pharmacol, 23: 72–78.PubMedCrossRefGoogle Scholar
  66. Scholz, W. and Albus, U., 1993, Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion, Basic Res. Cardiol, 88: 443–455.Google Scholar
  67. Sick, T.J., Whittingham, T.S., and LaManna, J.C., 1987, Evidence for multiple H+ pools and their significance for electrical function during anoxia in hippocampal slices, J. Cereb. Blood Flow Metab., 1 (suppl. 1): S113(Abstract).Google Scholar
  68. Siesjö, B.K., 1973, Metabolic control of intracellular pH, Scand. J. Clin. Lab. Invest, 32: 97–104.PubMedCrossRefGoogle Scholar
  69. Siesjö, B.K., 1988, Acidosis and ischemic brain damage, Neurochem. Pathol, 9: 31–88.Google Scholar
  70. Silver, I.A. and Erecinska, M., 1992, Ion homeostasis in rat brain in vivo: intra- and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia, J. Cereb. Blood Flow Metab., 12: 759–772.PubMedCrossRefGoogle Scholar
  71. Simon, R.P., Niiro, M., and Gwinn, R., 1993, Brain acidosis induced by hypercarbic ventilation attenuates focal ischemic injury, J. Pharmacol. Exp. Ther, 267: 1428–1431.PubMedGoogle Scholar
  72. Standen, N.B., Pettit, A.I., Davies, N.W, and Stanfield, P.R., 1992, Activation of ATP-dependent K+ currents in intact skeletal muscle fibres by reduced intracellular pH, Proc. Roy. Soc. Lond. B, 247: 195–198.CrossRefGoogle Scholar
  73. Staub, F., Baethmann, A., Peters, J., Weigt, H, and Kempski, O., 1990, Effects of lactacidosis on glial cell volume and viability, J. Cereb. Blood Flow Metab., 10: 866–876.PubMedCrossRefGoogle Scholar
  74. Swanson, R.A., 1992, Physiologic coupling of glial glycogen metabolism to neuronal activity in brain, Can. J. Physiol Pharmacol, 70: S138–S144.PubMedCrossRefGoogle Scholar
  75. Swanson, R.A., Morton, M.M., Sagar, S.M., and Sharp, F.R., 1992, Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography, Neurosci., 51: 451–461.CrossRefGoogle Scholar
  76. Tang, C.-M., Dichter, M., and Morad, M., 1990, Modulation of the N-methyl-D-aspartate channel by extracellular H+, Proc. Natl. Acad. Sci. USA, 87: 6445–6449.PubMedCrossRefGoogle Scholar
  77. Tombaugh, G.C. and Sapolsky, R.M., 1993, Evolving concepts about the role of acidosis in hypoxic/ischemic injury, J. Neurochem., 61: 793–803.PubMedCrossRefGoogle Scholar
  78. Trivedi, B. and Danforth, W.H., 1966, Effect of pH on the kinetics of frog muscle phosphofructokinase, J. Biol Chem., 241: 4110–4112.PubMedGoogle Scholar
  79. Urbanics, R., Leniger-Follert, E., and Lubbers, D.W., 1978, Time course of changes of extracellular H+ and K+ activities during and after direct electrical stimulation of the brain cortex, Pflüg. Arch., 378:47–53.CrossRefGoogle Scholar
  80. von Hanwehr, R., Smith, M.-L., and Siesjö, B.K., 1986, Extra- and intracellular pH during near-complete forebrain ischemia in the rat, J. Neurochem., 46: 331–339.CrossRefGoogle Scholar
  81. Widmer, H., Abiko, H., Faden, A.I., James, T.L., and Weinstein, RR., 1992, Effects of hyperglycemia on the time course of changes in energy metabolism and pH during global cerebral ischemia and reperfusion in rats: Correlation of *H and 31P NMR spectroscopy with fatty acid and excitatory amino acid levels, J. Cereb. Blood Flow Metab., 12: 456–468.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Joseph C. LaManna
    • 1
  1. 1.Department of Neurology Scool of MedicineCase Western Reserve UniversityClevelandUSA

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