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Hypoxia/Ischemia and the pH Paradox

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Oxygen Transport to Tissue XVII

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 388))

Abstract

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.

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References

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Blomqvist, P., Mabe, H., and Siesjö, B.K., 1982, Transient ischemia leads to intracellular alkalosis in the brain, Acta Physiol. Scand., 116: 103–104.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Busa, W.B. and Nuccitelli, R., 1984, Metabolic regulation via intracellular pH, Am. J. Physiol, 246: R409–R438.

    PubMed  CAS  Google Scholar 

  • Chesler, M., 1990, The regulation and modulation of pH in the nervous system, Prog. Neurobiol, 34: 401–427.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Crowell, J.W. and Kaufmann, B.N., 1961, Changes in tissue pH after circulatory arrest, Am. J. Physiol, 200: 743–745.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Dringen, R., Gebhardt, R., and Hamprecht, B., 1993, Glycogen in astrocytes: possible function as lactate supply for neighboring cells, Br. Res., 623: 208–214.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hansen, A.J., 1985, Effect of anoxia on ion distribution in the brain, Physiol. Rev., 65: 101–148.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hochachka, P.W. and Mommsen, T.P., 1983, Protons and anaerobiosis, Science, 219: 1391–1397.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Hossmann, K.-A., 1982, Treatment of experimental cerebral ischemia, J. Cereb. Blood Flow Metab., 2: 275–297.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Kaku, D.A., Giffard, R.G., and Choi, D.W., 1993, Neuroprotective effects of glutamate antagonists and extracellular acidity, Science, 260: 1516–1518.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  Google Scholar 

  • Keung, E.C. and Li, Q., 1991, Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes,/Clin. Invest., 88: 1772–1777.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Kraig, R.P., Ferreira-Filho, C.S., and Nicholson, C, 1983, Alkaline and acid transients in cerebellar microenvironment, J. Neurophysiol, 49: 831–850.

    CAS  Google Scholar 

  • Kraig, R.P. and Chesler, M., 1990, Astrocytic acidosis in hyperglycemic and complete ischemia, J. Cereb. Blood Flow Metab., 10: 104–114.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Moolenaar, W.H., 1986, Effects of growth factors on intracellular pH regulation, Ann. Rev. Physiol, 48: 363–376.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Nemoto, E.M. and Frinak, S., 1981, Brain tissue pH after global brain ischemia and barbiturate loading in rats, Stroke, 12: 77–82.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Plum, F, 1983, What causes infarction in ischemic brain?, Neurol, 33: 222–233.

    CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Scholz, W. and Albus, U., 1993, Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion, Basic Res. Cardiol, 88: 443–455.

    CAS  Google Scholar 

  • 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 

  • Siesjö, B.K., 1973, Metabolic control of intracellular pH, Scand. J. Clin. Lab. Invest, 32: 97–104.

    Article  PubMed  Google Scholar 

  • Siesjö, B.K., 1988, Acidosis and ischemic brain damage, Neurochem. Pathol, 9: 31–88.

    Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Swanson, R.A., 1992, Physiologic coupling of glial glycogen metabolism to neuronal activity in brain, Can. J. Physiol Pharmacol, 70: S138–S144.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Tombaugh, G.C. and Sapolsky, R.M., 1993, Evolving concepts about the role of acidosis in hypoxic/ischemic injury, J. Neurochem., 61: 793–803.

    Article  PubMed  CAS  Google Scholar 

  • Trivedi, B. and Danforth, W.H., 1966, Effect of pH on the kinetics of frog muscle phosphofructokinase, J. Biol Chem., 241: 4110–4112.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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LaManna, J.C. (1996). Hypoxia/Ischemia and the pH Paradox. In: Ince, C., Kesecioglu, J., Telci, L., Akpir, K. (eds) Oxygen Transport to Tissue XVII. Advances in Experimental Medicine and Biology, vol 388. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0333-6_36

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