Brain pH Research Articles

Effects of Hypoglycemia and Hypocarbia on Brain pH, ATP Phosphocreatine, and Blood Flow by NMR Spectroscopy

Effects of Hypoglycemia and Hypocarbia on Brain pH, ATP Phosphocreatine, and Blood Flow by NMR Spectroscopy

A bicarbonate-dependent increase in extracellular pH mediated by GABA A receptors in turtle cerebellum

The γ-aminobutyric acid (GABA)-gated anion channel has been found to have a significant permeability to bicarbonate in isolated nerve cells and crayfish muscle. We have studied the extracellular pH of the in vitro turtle cerebellum to determine whether the extracellular pH of vertebrate brain can be modulated by GABA. Exposure to 10 −3 M GABA produced an extracellular alkaline transient with a mean amplitude of 0.054 ± 0.19 pH units ( n = 49, range 0.018–0.091 pH units). The GABA-evoked alkaline shift was blocked by picrotoxin and was dependent on the presence of HCO 3 − in the bathing media. These data suggest that GABA A receptors gate an HCO 3 −-efflux which is sufficient to modulate brain pH.

Rapid Communication: Response of the Human Brain to a Hypercapnic Acid Load in Vivo

1. The aim of this investigation was to measure the change in intracellular pH of human brain in vivo in response to hypercapnia. 2. Five healthy male subjects inspired air for 20 min and then 5% CO2/95% O2 for 30 min, of which the first 10 min was used to achieve a steady-state end-tidal CO2 measurement. 3. 31P nuclear magnetic resonance spectroscopy was used to measure intracellular pH while breathing air and during hypercapnia. Simultaneous localization between superficial and deep brain was achieved by using the phase-modulated rotating frame imaging technique. One subject volunteered to breath air for a further phase-modulated rotating frame imaging study while recovering from hypercapnia. 4. End-tidal CO2 increased when breathing 5% CO2/95% O2 (on air, 5.57 +/- 0.21%; on 5% CO2/95% O2, 6.41 +/- 0.16%; rise = +0.84 +/- 0.09%; means +/- SEM) causing a reduction in brain intracellular pH, which was more pronounced in deep brain (5 cm = mainly white matter, from 7.02 +/- 0.006 pH units to 6.96 +/- 0.001 pH units, mean +/- SEM) than in superficial brain (2 cm = mainly grey matter, from 7.02 +/- 0.006 pH units to 7.00 +/- 0.006 pH units, mean +/- SEM). 5. The white matter responded to hypercapnia with a greater fall in intracellular pH than the grey matter. This could either be due to differences in blood flow between grey and white matter in response to hypercapnia or to differences in intracellular pH regulation/buffering between these two tissues.

Sudden infant death syndrome: pH and lactate in brain

Sudden infant death syndrome: pH and lactate in brain

Acid Homeostasis Following Partial Ischemia in Neonatal Brain Measured In Vivo by 31P and 1H Nuclear Magnetic Resonance Spectroscopy

The purpose of this study was to investigate neonatal brain energy metabolism, acid, and lactate homeostasis in the period immediately following partial ischemia. Changes in brain buffering capacity were quantified by measuring mean intracellular brain pH, calculated from the chemical shift of Pi, in response to identical episodes of hypercarbia before and after ischemia. In addition, the relationship between brain buffer base deficit and intracellular pH was compared during and following ischemia. Thus, in vivo 31P and 1H nuclear magnetic resonance spectra were obtained from the brains of seven newborn piglets exposed to sequential episodes of hypercarbia, partial ischemia, and a second episode of hypercarbia in the postischemic recovery period. For the first episode of hypercarbia, brain buffering was similar to values reported for adult animals of other species (percentage pH regulation = 54 +/- 16%). During ischemia, the brain base deficit per unit change in pH was -19 +/- 5 mM/pH unit, which is similar to values reported for adult rats. By 20-35 min postischemia, brain acidosis partly resolved in spite of a net increase in lactate concentration. Therefore, the consumption of lactate could not explain acid homeostasis in the first 35 min following ischemia. We conclude that H+/HCO3- or other proton equivalent translocation mechanisms must be sufficiently developed in piglet brain to support acid regulation. This is surprising, because a substantial body of evidence implies these processes would be less active in immature brain. The second episode of hypercarbia, from 35 to 65 min postischemia, resulted in a smaller decrease in brain pH compared with the first episode, a result indicating an increase in brain buffering capacity (percentage pH regulation = 79 +/- 29%). This was associated with a parallel decrease in brain lactate content, and therefore acid regulation could be attributed to either continued ion translocation or the consumption of lactate. A mild decrease in brain pH and content of energy metabolites was observed, a finding suggesting that the metabolic consequences of severe postischemic hypercarbia are neither particularly dangerous or beneficial.

Regional changes of tissue pH and ATP content in rat brain following systemic administration of kainic acid

Regional metabolic alterations induced by systemic administration of kainic acid were investigated in rat brains. The histochemical study revealed that an acidic pH shift preceded an ATP decrease in the limbic structures. In the hippocampal Ammon's horn, it was noted that a selective decrease of ATP occured in the dendritic subfield, such as the stratum radiatum and/or the stratum oriens. It was suggested that this selective ATP decrease in the dendrite is directly related to kainate neurotoxicity.

Characterization of Cerebral Energetics and Brain pH by 31P Spectroscopy after Graded Canine Cardiac Arrest and Bypass Reperfusion

Recovery of cerebral energy metabolism is used to indicate CNS viability after ischemia. This study utilized 31P nuclear magnetic resonance (NMR) spectroscopy to measure cerebral energy state and intracellular pH in dogs subjected to 8, 12, or 16 min of cardiac arrest and reperfusion using cardiopulmonary bypass. Spectra were obtained throughout ischemia and initial reperfusion and repeated at 30 and 144 h post ischemia. Neurologic deficit scoring was performed at 12 and 24 h post insult and then daily. High-energy phosphates were depleted by the end of all ischemic intervals. Recovery occurred within 60 min of reperfusion and persisted with no differences in the rate of return between groups (p greater than 0.05). Brain pH (pHb) decreased by the end of ischemia in all groups (p less than 0.0001). Neither the pHb nadir nor its recovery differed between groups (p greater than 0.05). Although longterm neurologic outcome differed between groups, the spectra were similar. Assessment of cerebral energy state using 31P NMR spectroscopy does not appear to be a sensitive indicator of neurologic outcome after global ischemia in dogs. Return of high-energy phosphates may be a necessary but not sufficient condition for cerebral recovery after ischemia. The return of high-energy phosphates after a 16-min cardiac arrest, however, indicates a potential for neurological recovery.

Extracellular pH in the Rat Brain during Hypoglycemic Coma and Recovery

It has previously been shown that hypoglycemic coma is accompanied by marked energy failure and by loss of cellular ionic homeostasis. The general proposal is that shortage of carbohydrate substrate prevents lactic acid formation and thereby acidosis during hypoglycemic coma. The objective of the present study was to explore whether rapid downhill ion fluxes, known to occur during coma, are accompanied by changes in extra- and/or intracellular pH (pHe and/or pHi), and how these relate to the de- and repolarization of cellular membranes. Cortical pHe was recorded by microelectrodes in insulin-injected rats subjected to 30 min of hypoglycemic coma, with cellular membrane depolarization. Some rats were allowed up to 180 min of recovery after glucose infusion and membrane repolarization. Arterial blood gases and physiological parameters were monitored to maintain normotension, normoxia, normocapnia, and normal plasma pH. Following depolarization during hypoglycemia, a prompt, rapidly reversible alkaline pHe shift of about 0.1 units was observed in 37/43 rats. Immediately thereafter, all rats showed an acid pH shift of about 0.2 units. This shift developed during the first minute, and pHe remained at that level until repolarization was induced. Following repolarization, there was an additional, rapid, further lowering of pHe by about 0.05 units, followed by a more prolonged decrease in pHe that was maximal at 90 min of recovery (delta pHe of approximately -0.4 units). The pHe then slowly normalized but was still decreased (-0.18 pH units) after 180 min when the experiment was terminated. The calculated pHi showed no major alterations during hypoglycemic coma or after membrane repolarization following glucose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain pH in acute isocapnic metabolic acidosis and hypoxia: a 31P-nuclear magnetic resonance study

It is well known that brain pH changes rapidly in acute hypercapnia or hypocapnia. The effect of acute isocapnic metabolic acid-base change on brain pH is less certain. To study this problem, acute isocapnic metabolic acidosis was induced by HCl or lactic acid infusions in rats, and recovery from acidosis was accomplished by NaHCO3 infusion. Brain pH was measured by 31P-nuclear magnetic resonance. Despite decreases in blood pH of 0.34 and 0.36 units, respectively, in less than 1 h of acid infusion and rapid recovery during bicarbonate infusion, brain pH was unaffected (ranging between 7.08 and 7.11) and was uncorrelated with blood pH. The blood pH minus brain pH gradient was eliminated by the acidosis. By contrast, hypoxia-induced endogenous lactic acidosis lowered blood and brain pH equivalently, but the fall in brain pH preceded that in blood. During normoxic recovery, brain pH overshot and became alkaline when blood pH was still significantly reduced and blood lactate levels were markedly elevated. Presumably, this is due to stimulated active H+ transport. The results demonstrate that brain pH is affected differently in metabolic, respiratory, and endogenous acid-base disturbances. Thus brain pH cannot be predicted solely from blood pH values.

Synthesis and tissue distribution of four Se-labeled tertiary amines, potential brain pH imaging agents

Four new tertiary amines: bis(3- N,N-dimethyl aminopropyl)selenide (PROMOSE), bis(3- N-(morpholino) propyl)selenide, N-methyl-selenomorpholine and N-phenyl-selenomorpholine structurally related to MOSE proposed by Kung and Blau, have been labeled through a radiochemical procedure suitable for both 75Se and 73Se. The radiochemical yields of the carrier added synthesis ranged between 64 and 85% for the four 75Se labelings and was 64% EOB time corrected for [ 73Se]PROMOSE. The chemical and radiochemical purities were higher than 99% after chromatographic purifications. The n-octanol/ phosphate buffer partition coefficients ( P) were measured at various pH (6.5–8) for each compound and the tissue distributions of PROMOSE in rats were also carried out. The experimental results showed a good correlation between the P = f( pH) function and the in vivo behaviour of the considered compound. PROMOSE was selected for further investigations as a brain pH indicator.

The Novel Dihydronaphthyridine Ca2+ Channel Blocker CI-951 Improves CBF, Brain pHi, and EEG Recovery in Focal Cerebral Ischemia

The effects of the novel dihydronaphthyridine Ca2+ antagonist CI-951 on focal cerebral ischemia were assessed during MCA occlusion in 30 white New Zealand rabbits under 1.0% halothane anesthesia. In vivo brain pHi and focal CBF were measured with umbelliferone fluorescence. Baseline normocapnic brain pHi and CBF were 7.02 +/- 0.02 and 48.4 +/- 2.9 ml/100 g/min, respectively. In the severe ischemic regions, 15 min postocclusion brain pHi and CBF were 6.62 +/- 0.04 and 14.4 +/- 0.7 ml/100 g/min in controls vs. 6.60 +/- 0.02 and 12.9 +/- 2.3 ml/100 g/min, respectively, in animals destined to receive CI-951. Twenty minutes after MCA occlusion, CI-951 was administered at 0.5 microgram/kg/min and brain pHi and CBF were determined in both regions of severe and moderate ischemia for 4 h postocclusion. Control severe ischemic sites demonstrated no significant improvement in brain pHi and only mild increases in CBF over the next 4 h. CI-951 caused significant improvement in both of these parameters. Postocclusion 4 h brain pHi and CBF measured 6.69 +/- 0.04 and 18.5 +/- 3.2 ml/100 g/min in controls vs. 7.01 +/- 0.04 and 41.7 +/- 5.3 ml/100 g/min, respectively, in CI-951 animals (p less than 0.001). Similar improvements were observed in moderate ischemic sites. In animals that demonstrated postocclusion EEG attenuation, 75% of CI-951 animals had EEG recovery as compared to 18% in controls. CI-951 may be a useful therapeutic agent for focal cerebral ischemia if histological and outcome studies verify these data.

Intracellular pH during daily torpor inPeromyscus maniculatus

Intracellular and extracellular acid-base parameters during normothermy and daily torpor were examined in deer mice (Peromyscus maniculatus). [14C]Dimethyloxazolidinedione and [3H]inulin were used to assess intracellular pH in liver, heart, skeletal muscle, and brain. Buffering capacities were determined using tissue homogenates. A significant increase in plasma PCO2 and CCO2 during daily torpor indicates a respiratory acidosis. All tissues experienced a reduction in the calculated dissociation ratio of histidine imidazole groups (alpha imid) during daily torpor (16.5% for brain, approximately 10% for other tissues). Based on comparisons with physicochemical tissue buffering capacities, metabolic compensation of the respiratory acidosis occurred in liver, heart, and plasma, while brain was more acidotic than predicted. The more extensive change in brain alpha imid might influence a regulated decrease in body temperature. Comparison of acid-base parameters during daily torpor and hibernation suggests that the magnitude of acid-base modifications in mammals may be associated with the level of dormancy.

An in vivo examination of rat brain during sepsis with 31P-NMR spectroscopy.

Neurological symptoms including lethargy, obtundation, and confusion are early and common findings in patients with sepsis. The etiology of the mental status changes that occur during severe infection is not known. We investigated the effects of sepsis on the levels of high-energy phosphates to determine whether decreased energy metabolism was a factor in the depressed neurological state. The time course of changes in brain pH and brain high-energy phosphate metabolites during an Escherichia coli infusion was determined from sequential phosphorus-31 nuclear magnetic resonance (31P-NMR) spectra of ketamine-xylazine-anesthetized rats. A second group of rats received 0.9% saline infusion and served as a control group. Despite severe obtundation and near loss of righting reflex, the rats in the septic group had no significant differences in the brain pH, the ratio of phosphocreatine (PCr) to beta-adenosine 5'-triphosphate (beta-ATP), or in the ratio of PCr to Pi. The only significant decrease in brain high-energy phosphates or pH occurred terminally in the septic rat group and corresponded with a rapidly falling arterial blood pressure. We conclude that the severe neurological depression that is characteristic of sepsis is not due to decreased levels of brain high-energy phosphates or brain acidosis.

Brain pH effects of NaHCO3 and Carbicarb® in lactic acidosis

The effects of iv sodium bicarbonate (NaHCO3) and Carbicarb, an experimental buffer, were compared in a rat model of lactic acidosis induced by controlled hemorrhage and asphyxia. Although both NaHCO3 and Carbicarb were effective at alkalinizing the arterial blood in this model, NaHCO3 administration resulted in a rise in PaCO2 where Carbicarb did not (+9 +/- 2 vs. +2 +/- 2 torr at 2 min after infusion, p less than .01). Moreover, NaHCO3 resulted in a small decrease in intracellular brain pH as measured with P-31 nuclear magnetic resonance where Carbicarb afforded intracellular brain alkalinization (-0.03 +/- 0.01 vs. +0.08 +/- 0.02 pH units at 2 min, p less than .01). If these data are confirmed clinically, Carbicarb may offer advantages over NaHCO3 under conditions of fixed or limited ventilation.

NMR spectroscopic investigation of the recovery of energy and acid-base homeostasis in the cat brain after prolonged ischemia.

The effects of 1 h of complete global ischemia on the recovery of high-energy phosphates, intracellular pH (pHi), and lactate in the cat brain in vivo was investigated by 31P and 1H NMR spectroscopy. Ischemia led to a decrease in creatine phosphate (CrP), nucleoside triphosphates (NTP), and pHi, while inorganic phosphate and lactate increased. Intracellular pH decreased from a control value of 7.07 +/- 0.04 to 6.17 +/- 0.12 after 1 h of ischemia (N = 7). The degree of metabolic recovery after recirculation was variable. In three animals CrP and NTP were detected within 4 min and NTP increased to greater than or equal to 90% of control within 1 h; these levels were maintained for the 3 h of observation. In four other animals, CrP and NTP reached only 20 to 80% of control; however, high-energy phosphates decreased and lactate increased spontaneously between 1 and 2.5 h. Immediately following recirculation, pHi decreased further by an average of 0.3 units. The rate of recovery of cerebral pHi was slower than that of PCr and NTP for the majority of animals. Recovery of pHi was not detected for an average of 32 min after recirculation--by this time, NTP had attained 80 +/- 10% of their preischemic level. Recovery of pHi (and lactate) was not observed in two animals where PCr and NTP recovered transiently to only 30-43% of the preischemic level. Recovery of cerebral pHi was markedly heterogeneous in one animal, since two Pi peaks were detected shortly after recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of hyperthermic ischemic acidosis by a conditioning event in cats.

We investigated the effects of multiple episodes of cerebral ischemia on intracellular brain pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Four cats were subjected to two 16-minute episodes of complete global cerebral ischemia 6 hours apart; the second episode occurred under hyperthermic conditions (mean +/- SD body temperature 40.8 +/- 0.4 degrees C). Intracellular pH in these four cats was compared with that in nine cats subjected to a single 16-minute episode of complete global cerebral ischemia under hyperthermic conditions (mean +/- SD body temperature 40.6 +/- 0.2 degrees C). Intracellular pH during hyperthermic recirculation was significantly (p less than 0.03) greater in cats subjected to a previous ischemic event than that in cats subjected to only a single hyperthermic ischemic event. We speculate that the induction of heat shock proteins by an initial ischemic event may protect brain tissue from further ischemic insult.

Effects of various catecholamines on high-energy phosphates of rat liver and brain during hemorrhagic shock measured by 31P-NMR spectroscopy.

The effects of dopamine, epinephrine and norepinephrine on energy metabolism as well as intracellular pH in rat liver and brain during hemorrhagic shock were examined by in vivo 31P-NMR spectroscopy. The hemorrhagic shock was induced by arterial bleeding to a mean arterial pressure (MAP) of 30-40 mmHg. Upon the induction of hemorrhagic shock, there was a dramatic fall in adenosine triphosphate (ATP) and a rise in inorganic phosphate (Pi) in the liver. The intracellular pH indicated severe acidosis. However, no change in these parameters was observed in the brain during hemorrhagic shock. After infusion of the above catechollamines following 10 min of hemorrhagic shock, MAP increased to 90-100% of its control value. Only dopamine improved hepatic energy metabolism, whereas brain energy metabolism was not affected by any of them. This suggests that dopamine protects liver function during hemorrhagic shock without affecting brain energy metabolism.

Effect of Hypoglycemia and Hypocarbia and Brain pH, ATP, Phosphocreatine and Blood Flow

Effect of Hypoglycemia and Hypocarbia and Brain pH, ATP, Phosphocreatine and Blood Flow

Brain pH responses to sodium bicarbonate and Carbicarb during systemic acidosis

Rats subjected to ammonium chloride-induced metabolic acidosis or respiratory acidosis caused by hypercapnia were given alkalinization therapy with either sodium bicarbonate or Carbicarb. Ammonium chloride induced dose-dependent systemic acidosis but did not affect intracellular brain pH. Hypercapnia caused dose-dependent systemic acidosis as well as decreases in intracellular brain pH. Sodium bicarbonate treatment resulted in systemic alkalinization and increases in arterial PCO2 in both acidosis models, but it caused intracellular brain acidification in rats with ammonium chloride acidosis. Carbicarb therapy resulted in systemic alkalinization without major changes in arterial PCO2 and intracellular brain alkalinization in both acidosis models. These data demonstrate that bicarbonate therapy of systemic acidosis may be associated with "paradoxical" intracellular brain acidosis, whereas Carbicarb causes both systemic and intracellular alkalinization under conditions of fixed ventilation.

Pharmacological basis for the use of nimodipine in central nervous system disorders

Nimodipine, a Ca2+ antagonist with cerebrovasodilatory and anti-ischemic effects, binds to rat, guinea pig, and human brain membranes with high affinity (less than 1 nM). Only at higher concentrations has nimodipine been reported to block the release of some neurotransmitters and hormones from neuronal tissue. Nimodipine has no consistent effect on brain oxygen consumption or cortical ATP or phosphocreatine levels, although the ischemia-induced fall of brain ATP levels in gerbils or the lowering of intracellular brain pH in rabbits with focal cerebral ischemia were antagonized by the drug. In rats and baboons with middle cerebral artery occlusion, nimodipine was found to reduce neurological deficits without an increase in intracranial pressure or brain edema. Electrophysiological studies with nimodipine suggested a direct neuronal action. In rabbit dorsal root ganglion cells, concentrations as low as 20 nM were reported to block inward Ca2+ currents. Recent studies have suggested that nimodipine may also improve memory in brain-damaged or old rats, restore sensorimotor function and abnormal walking patterns of old rats, and accelerate acquisition of associative learning in aging rabbits. Blockade of age-related changes in Ca2+ fluxes in rat hippocampal neurones by nimodipine in vitro pointed to neuronal plasma membrane as the site of nimodipine action. The therapeutic usefulness of nimodipine appears not to be limited to cerebral ischemia, but may include dementia, age-related degenerative diseases, epilepsy, and ethanol intoxication.