sodium-bicarbonate and Brain-Ischemia

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bicarbonates; Blood Circulation; Brain Ischemia; Cardiotonic Agents; Child; Electric Countershock; Heart Arrest; Heart Massage; Humans; Hypoxia, Brain; Infant, Newborn; Resuscitation; Sodium Bicarbonate; Ventricular Fibrillation

Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO2 for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO2 for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO3 significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen-glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis.

Topics: Acidosis; Animals; Brain Ischemia; Carbon Dioxide; Male; Mice; Neuroprotective Agents; Reperfusion Injury; Sodium Bicarbonate; Stroke

Acid-sensing ion channels (ASICs), newly discovered members of epithelial Na+ channels/degenirin superfamily, are widely distributed throughout the mammalian peripheral and central nervous system and have been implicated in many physiological and pathophysiological processes. We have recently shown that activation of calcium-permeable ASIC1a is involved in acidosis-mediated, glutamate independent, ischaemic brain injury. In this study the neuroprotective time window for ASIC1a blockade in a mouse model of focal ischaemia is examined and the role of acidosis per se addressed by continuous pH measurements in penumbral cortex and post-ischaemic alkalization of brain. The effects of NMDA receptor blockade and ASIC1a blockade were compared. Specific ASIC1a blockade by the tarantula toxin psalmotoxin, PcTX, administered intracerebroventricularly as late as 5 h after 60 min of transient middle cerebral artery occlusion (MCAO) reduced infarct volume by >50%; the protection persisted for at least 7 days. Protection was also demonstrated after permanent MCAO. In penumbral cortex alkaline pH preceded acid pH and infarction. Attenuating brain acidosis by NaHCO3 or blocking ASIC1a with PcTX were both protective. NMDA blockade produced additive neuroprotection and the presence of PcTX prolonged the time window of effectiveness of NMDA blockade. Neuroprotection by PcTX was also achievable by intranasal administration. These findings further suggest that ASIC1a is a novel molecular target involved in ischaemic brain injury. Post-ischaemic administration of an ASIC1a blocker may prove to be an effective neuroprotective strategy for stroke patients.

Topics: Acid Sensing Ion Channels; Acidosis; Animals; Brain; Brain Ischemia; Cerebral Cortex; Cerebral Ventricles; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Infarction, Middle Cerebral Artery; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; N-Methylaspartate; Nerve Tissue Proteins; Neuroprotective Agents; Sodium Bicarbonate; Sodium Channels; Spider Venoms; Time Factors

It has been demonstrated in many studies that intracellular brain acidosis during cerebral ischemia is a significant factor in perpetuating the cycle of cellular dysfunction leading to neuronal injury. The purpose of this study was to determine whether preischemic administration of alkalotic agents could reduce neuronal injury after focal cerebral ischemia.. Fifteen fasted rabbits under 1.0% halothane anesthesia were randomized into three groups: Group 1 rabbits were ischemic controls (n = 5) that underwent 4 hours of focal cerebral ischemia. Groups 2 and 3 rabbits underwent a paradigm similar to that of Group 1, except that they were pretreated with either sodium bicarbonate or Carbicarb at similar buffering capacities. Intracellular brain pH (pH(i)), regional cortical blood flow (rCBF), and intrinsic reduced nicotinamide adenine dinucleotide (NADH) fluorescence were measured with in vivo fluorescence imaging. At the end of each experiment, infarct volume expressed as a percentage of hemispheric volume was measured by triphenyltetrazolium chloride staining.. Preischemic alkalinization did not alter brain pH(i), rCBF, or NADH fluorescence. After 4 hours of ischemia, brain pH(i), rCBF, NADH fluorescence, and infarct volume measured 6.40 +/- 0.09 (mean +/- standard error), 11 +/- 2 ml/100 g/min, 165 +/- 8% of baseline control, and 37 +/- 3% in ischemic controls, respectively. In Group 2 animals treated with sodium bicarbonate, brain pH(i), rCBF, NADH fluorescence, and infarct volume improved significantly (P < 0.05, analysis of variance) to 6.74 +/- 0.08, 24 +/- 6 ml/100 g/min, 137 +/- 6% of baseline control, and 22 +/- 4%, respectively. Group 3 Carbicarb animals demonstrated improvements in brain pH(i), rCBF, and NADH fluorescence, with a significant reduction in infarct volume.. These findings suggest that pretreatment with alkalinizing agents may be a useful intervention to provide intraoperative cerebral protection from ischemic injury.

Topics: Alkalies; Animals; Brain; Brain Ischemia; Carbonates; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Drug Combinations; Hydrogen; Hydrogen-Ion Concentration; NAD; Neuroprotective Agents; Oxidation-Reduction; Rabbits; Sodium Bicarbonate

Controversy surrounds the use of buffers during cardiac arrest to correct acidosis. The objective of this study was to determine whether attenuation or neutralization of cerebral acidosis by Carbicarb alters hippocampal glutamate levels, neuronal cell death, and neurologic deficits after reperfusion from asphyxial cardiac arrest in rats.. Rats were prospectively randomized to either a control (n=45), low-dose Carbicarb (LDC; 3 mL/kg, n=45), or high-dose Carbicarb (HDC; 6 mL/kg, n=45) group in a blinded fashion during resuscitation after 8 minutes of asphyxial cardiac arrest. Microdialysis was used to assess brain pH and glutamate. A neurologic deficit score and neuronal cell death in the hippocampus were determined at day 7.. Resuscitation was greatest in LDC rats (42/45) and least in HDC rats (28/45) versus that in control rats (34/45). Brain pH was higher in the LDC and HDC rats 10 minutes after resuscitation and remained higher than that of control rats for 120 minutes after resuscitation. Glutamate levels at 10 to 120 minutes after reperfusion were lowest in the LDC rats. LDC rats had the lowest neurologic deficit score (1+/-2) versus that of control rats (13+/-8) and HDC rats (19+/-6). Hippocampal neuronal cell death was lowest in LDC rats (30+/-20) versus that in control rats (86+/-47) and HDC rats (233+/-85).. LDC administered during resuscitation from asphyxial cardiac arrest attenuated acidosis, improved resuscitation, and reduced neurologic deficits and the number of dead hippocampal neurons. Neutralization of cerebral acidosis with HDC increased the number of dead hippocampal neurons and neurologic deficits after resuscitation from cardiac arrest in rats.

Topics: Acidosis; Animals; Asphyxia; Brain; Brain Ischemia; Carbonates; Cell Death; Disease Models, Animal; Drug Combinations; Glutamic Acid; Heart Arrest; Hippocampus; Neurons; Rats; Recovery of Function; Reperfusion Injury; Sodium Bicarbonate; Treatment Outcome

In vitro data suggest that low tissue pH reduces, whereas extracellular alkalosis potentiates, cerebral anoxic injury via excitotoxic mechanisms. We tested the hypothesis that in vivo metabolic alkalemia potentiates defects in energy metabolism after global incomplete cerebral ischemia (12 min) and reperfusion (180 min) by an N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. Brain ATP, phosphocreatine, and intracellular pH (pHi) were measured by 31P magnetic resonance spectroscopy in anesthetized dogs treated with 1) preischemic intravenous carbicarb buffer (NaHCO3+Na2CO3, Carb, n = 7); 2) carbicarb infusion plus NMDA receptor antagonist MK-801 (MK-801 + Carb, n = 7); 3) an osmotically equivalent volume of 5% NaCl (NaCl, n = 8); or 4) equivalent volume of 0.9% NaCl (Sal, n = 3). Sagittal sinus pH was raised to 7.82 +/- 0.04 before and 7.65 +/- 0.03 during ischemia in Carb vs. 7.72 +/- 0.01 and 7.60 +/- 0.01 in MK-801+Carb, 7.25 +/- 0.02 and 7.15 +/- 0.03 in NaCl, and 7.31 +/- 0.00 and 7.26 +/- 0.01 in Sal, respectively. Ischemic cerebral blood flow (CBF, radiolabeled microspheres), pHi, and ATP reduction were similar among groups. By 180 min of reperfusion, recovery of ATP was greater in MK-801+Carb (104 +/- 6% of baseline), NaCl (93 +/- 6%), and Sal (94 +/- 6%) than in Carb (47 +/- 6%). Intraischemic pHi was similar among groups, and pHi recovery did not vary among groups despite differences in sagittal sinus pH. In Carb, CBF was restored but with delayed hypoperfusion. We conclude that extracellular alkalosis is deleterious to postischemic CBF and energy metabolism, acting by NMDA receptor-mediated mechanisms.

Topics: Adenosine Triphosphate; Alkalies; Animals; Blood Pressure; Brain; Brain Ischemia; Carbonates; Cerebrovascular Circulation; Cranial Sinuses; Dizocilpine Maleate; Dogs; Drug Combinations; Evoked Potentials, Somatosensory; Hydrogen-Ion Concentration; Male; Osmolar Concentration; Receptors, N-Methyl-D-Aspartate; Reperfusion; Sodium Bicarbonate; Sodium Chloride

To assess the role of nitric oxide (NO) in cerebral ischemia, we investigated the effect of L-arginine, a substrate of NO synthase (NOS), and NG-nitro-L-arginine (L-NNA), a NOS inhibitor, on neuronal death in the CA1 hippocampal region. Seventy-two Mongolian gerbils were used in the study. Both carotid arteries were occluded for 4 min to induce forebrain ischemia. Temporal muscle temperature was strictly maintained at 37.5 +/- 0.3 degrees C during the ischemia. L-arginine (10 and 100 mg kg-1) or L-NNA (1, 10 and 100 mg kg-1) was administered intraperitoneally 4 times: 30 min before, 3 h, 6 h and 24 h after induction of ischemia. Four days after ischemic insult, the animals were perfusion-fixed, and the neuronal densities in the medial, middle and lateral CA1 subfield were estimated. Average neuronal cell density of the control group was 2-3 mm in each subfield. L-arginine at doses of 10 and 100 mg kg-1 did not prevent neuronal death. L-NNA at doses of 1 and 10 mg kg-1 did not protect neuronal cells from ischemia either. However, in ischemia gerbils treated with 100 mg kg-1 L-NNA, the average neuronal cell density in the lateral CA1 subfield was 54.4 +/- 19.1, L-NNA (100 mg kg-1) significantly (p < 0.05) reduced the occurrence of neuronal death in the lateral CA1 subfield. The present results suggest that NO plays an important role in the development of neuronal injury after global ischemia.

Topics: Animals; Arginine; Body Temperature; Brain Ischemia; Cell Death; Enzyme Inhibitors; Gerbillinae; Hippocampus; Male; Neurons; Nitric Oxide Synthase; Nitroarginine; Sodium Bicarbonate

We investigated the factors associated with cerebral dysfunction in patients undergoing extracorporeal life support (ECLS) following conventional advanced cardiac life support (ACLS). The subjects were 9 patients in whom ECLS was started following ACLS because of intractable cardiac arrest. We investigated whether the irreversibility of cerebral dysfunction during ECLS was related to the cardiopulmonary resuscitation (CPR) time, arterial pH and blood gases, hemoglobin concentration (Hb), peak arterial pressure (PAP) before the start of ECLS and total doses of epinephrine and sodium bicarbonate administered during CPR. Two of the 3 patients who recovered consciousness were weaned from ECLS and survived, while all 6 patients who did not recover from coma were not weaned and died. There was no difference in the CPR time, Hb and PAP before the start of ECLS along with total doses of epinephrine and sodium bicarbonate administered during CPR between the patients who recovered consciousness and those who did not. In addition, there was no difference in arterial pH and blood gases except the arterial oxygen tension (PaO2) between the groups. The PaO2 values before the start of ECLS in the patients who remained in coma ranged from 34 to 58 mmHg, whereas those in the patients who recovered consciousness ranged from 132 to 442 mmHg. The PaO2 values before the start of ECLS in the patients who remained in coma were less than 60 mmHg, whereas those in the patients who recovered consciousness were over 60 mmHg. The present study suggests that hypoxemia during CPR may play a major role in severe cerebral dysfunction in patients undergoing ECLS and PaO2 during CPR.

Topics: Adult; Blood Gas Analysis; Blood Pressure; Brain Ischemia; Cardiopulmonary Resuscitation; Case-Control Studies; Coma; Epinephrine; Extracorporeal Membrane Oxygenation; Female; Heart Arrest; Hemoglobins; Humans; Hydrogen-Ion Concentration; Hypoxia; Male; Middle Aged; Risk Factors; Sodium Bicarbonate; Time Factors

We investigated the immediate effect of tris (hydroxymethyl) aminomethane (THAM) and NaHCO3 on focal cerebral ischemia produced by occlusion of the left middle cerebral artery (MCA) in cats. The animals were divided into three groups. In the control group, physiological saline was infused continuously. The THAM and NaHCO3 groups received continuous administration of 0.3 mol THAM and 7% NaHCO3, respectively, to normalize arterial pH. Local CBF measured in the marginal and suprasylvian gyri decreased less than 30 ml/100 g/min after the MCA occlusion and there were no significant differences among the three groups. Extracellular pH of the marginal gyrus (peri-infarct zone) decreased from 7.21 to 6.86 in the control group. However, extracellular pH did not show significant changes in the THAM and NaHCO3 groups. Intracellular pH of the infarct area decreased from 7.23 to 6.13 in the control group within 6 hours after occlusion. THAM had a tendency to normalize intracellular pH compared with that in the control and NaHCO3 groups. THAM significantly (p < 0.05) decreased water content of the gray matter in the marginal gyrus at 6 hours after occlusion and the infarct size compared with those in the control and NaHCO3 groups. Therefore, normalization of systemic and perifocal acidosis with THAM is effective for reducing cortical edema and infarct size in the early stage of focal cerebral ischemia probably due to the improvement of intracellular acidosis.

Topics: Acid-Base Equilibrium; Animals; Brain Edema; Brain Ischemia; Cats; Cerebral Cortex; Cerebral Infarction; Extracellular Space; Intracellular Fluid; Sodium Bicarbonate; Tromethamine

Metabolic acidosis in cerebral ischemia is considered deleterious to cell function and neurological outcome. Amelioration of systemic and focal cerebral acidosis by an alkalizing agent may reduce ischemic brain damage. The effects of 0.3 mol tris (hydroxymethyl)aminomethane (THAM) and 7% NaHCO3 on focal cerebral ischemia produced by occlusion of the middle cerebral artery (MCA) in cats were examined. In thirty six adult cats, adjustment was made so that PaO2 and PaCO2 would be maintained within the normal range with mechanical ventilation and oxygen inhalation. Focal cerebral ischemia was produced by coagulation of the left MCA using the transorbital approach. The animals were divided into 3 groups as follows. 1) The control group received continuous intravenous administration of physiological saline (2 ml/kg/hour). 2) The THAM group received continuous intravenous administration of 0.3 mol THAM (2 ml/kg/hour). 3) The NaHCO3 group received continuous intravenous administration of 7% NaHCO3 (0.7 ml/kg/hour)+physiological saline (1.3 ml/kg/hour). PaO2, PaCO2 and mean arterial blood pressure were maintained within the normal range in each group. In the THAM and NaHCO3 groups, arterial pH was maintained within the normal range, whereas in the control group, arterial pH gradually decreased from 7.42 +/- 0.04 to 7.30 +/- 0.09 at 6 hours after MCA occlusion. Intracellular pH, measured by magnetic resonance spectroscopy over the ischemic brain, decreased from 7.23 +/- 0.06 to 6.13 +/- 0.61 by MCA occlusion. In the THAM group, intracellular pH increased compared with that in the control and 7% NaHCO3 group. These values, however, were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animals; Bicarbonates; Blood Pressure; Body Water; Brain; Brain Edema; Brain Ischemia; Cats; Cerebral Infarction; Sodium; Sodium Bicarbonate; Tromethamine

Serum lactic acidosis is characterized by a pH less than 7.25 and lactate greater than 5 mEq. Although sodium bicarbonate (NaHCO3) is standard treatment for this condition, clinical and experimental studies suggest that high doses of NaHCO3 may be ineffectual or even detrimental to brain, cardiovascular, and respiratory function, as well as survival. For this reason, low dose therapy with NaHCO3 has been recommended. Sodium dichloroacetate (NaDCA) has been used successfully to treat clinical and experimentally-induced lactic acidosis. The present study was designed to compare the effects of low dose NaHCO3 with NaDCA on blood pressure, blood chemistries and brain metabolites in rats with a low flow-induced (Type A, the most common type) lactic acidosis. Fasted male Wistar rats were subjected to cerebral ischemia and systemic hypotension for 30 min at which time, if the pH or HCO-3 fell to 7.2 or 10, respectively, the rat was treated with NaHCO3, NaDCA, or an equal volume of sterile water. Over the 30 min of recirculation that followed ischemia, treatment had no effect on blood pressure or glucose or on brain glucose or glycogen. NaHCO3 had no effect on lactate but appeared to stabilize pH and increase HCO3- more than in sham- or NaDCA-treated rats. Although NaDCA caused a greater increase in HCO3- than sham treatment, pH continued to decline. However, lactate decreased more in NaDCA- than in sham- or NaHCO3- treated rats. These results suggest that low dose NaHCO3 is not detrimental in this model; however, although NaHCO3 stabilized pH, it did not rapidly correct the acidosis. NaDCA at this dose had no effect on the acidosis but was effective in decreasing lactate. Since serum lactate has previously correlated with survival and since higher doses of NaDCA have corrected lactic acidosis in other studies, future evaluation of postischemic treatment with higher doses of NaDCA is warranted.

Topics: Acetates; Acidosis, Lactic; Animals; Bicarbonates; Blood Glucose; Brain Chemistry; Brain Ischemia; Dichloroacetic Acid; Glycogen; Lactates; Male; Rats; Rats, Inbred Strains; Resuscitation; Sodium; Sodium Bicarbonate