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.
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.
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.
Blomqvist, P., Mabe, H., and Siesjö, B.K., 1982, Transient ischemia leads to intracellular alkalosis in the brain, Acta Physiol. Scand., 116: 103–104.
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.
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.
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.
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.
Busa, W.B. and Nuccitelli, R., 1984, Metabolic regulation via intracellular pH, Am. J. Physiol, 246: R409–R438.
Chesler, M., 1990, The regulation and modulation of pH in the nervous system, Prog. Neurobiol, 34: 401–427.
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.
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.
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.
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.
Crowell, J.W. and Kaufmann, B.N., 1961, Changes in tissue pH after circulatory arrest, Am. J. Physiol, 200: 743–745.
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.
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.
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.
Dringen, R., Gebhardt, R., and Hamprecht, B., 1993, Glycogen in astrocytes: possible function as lactate supply for neighboring cells, Br. Res., 623: 208–214.
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.
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.
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):.
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.
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.
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.
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.
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.
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.
Hansen, A.J., 1985, Effect of anoxia on ion distribution in the brain, Physiol. Rev., 65: 101–148.
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.
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.
Hochachka, P.W. and Mommsen, T.P., 1983, Protons and anaerobiosis, Science, 219: 1391–1397.
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):.
Hossmann, K.-A., 1982, Treatment of experimental cerebral ischemia, J. Cereb. Blood Flow Metab., 2: 275–297.
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.
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.
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.
Kaku, D.A., Giffard, R.G., and Choi, D.W., 1993, Neuroprotective effects of glutamate antagonists and extracellular acidity, Science, 260: 1516–1518.
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).
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.
Keung, E.C. and Li, Q., 1991, Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes,/Clin. Invest., 88: 1772–1777.
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.
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.
Kraig, R.P., Ferreira-Filho, C.S., and Nicholson, C, 1983, Alkaline and acid transients in cerebellar microenvironment, J. Neurophysiol, 49: 831–850.
Kraig, R.P. and Chesler, M., 1990, Astrocytic acidosis in hyperglycemic and complete ischemia, J. Cereb. Blood Flow Metab., 10: 104–114.
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).
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
Moolenaar, W.H., 1986, Effects of growth factors on intracellular pH regulation, Ann. Rev. Physiol, 48: 363–376.
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.
Nemoto, E.M. and Frinak, S., 1981, Brain tissue pH after global brain ischemia and barbiturate loading in rats, Stroke, 12: 77–82.
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.
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.
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.
Plum, F, 1983, What causes infarction in ischemic brain?, Neurol, 33: 222–233.
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.
Scholz, W. and Albus, U., 1993, Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion, Basic Res. Cardiol, 88: 443–455.
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).
Siesjö, B.K., 1973, Metabolic control of intracellular pH, Scand. J. Clin. Lab. Invest, 32: 97–104.
Siesjö, B.K., 1988, Acidosis and ischemic brain damage, Neurochem. Pathol, 9: 31–88.
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.
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.
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.
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.
Swanson, R.A., 1992, Physiologic coupling of glial glycogen metabolism to neuronal activity in brain, Can. J. Physiol Pharmacol, 70: S138–S144.
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.
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.
Tombaugh, G.C. and Sapolsky, R.M., 1993, Evolving concepts about the role of acidosis in hypoxic/ischemic injury, J. Neurochem., 61: 793–803.
Trivedi, B. and Danforth, W.H., 1966, Effect of pH on the kinetics of frog muscle phosphofructokinase, J. Biol Chem., 241: 4110–4112.
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.
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.
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.
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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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