Specific quisqualate receptor ligand blocks both kainate and quisqualate responses.
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Animals↗
Biomedical subjects
A J Hansen
Publications and source records attributed to A J Hansen.
Brain interstitial composition during acute hyponatremia.
Brain cortical water spaces were determined in rat brain following an intraperitoneal infusion of distilled water (15% of body weight). Total water content was determined by gravimetric methods while the size of the interstitial space and the interstitial ion concentrations were measured by ion-selective microelectrodes. Ion content of brain gray matter and plasma were determined by standard methods. During 2 h the plasma osmolarity changed from 301 to 251 mosmol/l while cortical water content increased from 4.04 ml/g dry weight (gdw) to 4.42 ml/gdw. It was observed that the size of the interstitial space remained stable during the two hours of osmotic challenge. Although the brain showed a volume regulatory response by an outward transport of ions, it was not sufficient since there was an increase of brain volume of 10%. The accumulated water was distributed in the interstitial and intracellular compartments according to their individual sizes. It is concluded that cells in brain gray matter are not able to regulate their volume in cytotoxic brain oedema.
Acute Disease↗
Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge.
The present study aimed to study the relation between the release of arachidonic acid (AA) and the energy state in cerebral cortices of rats during single episodes of cortical spreading depression (CSD). The changes in concentrations of AA, labile phosphate compounds [ATP, ADP, AMP, and phosphocreatine (PCr)], and glycolytic metabolites (lactate, pyruvate, glucose, and glycogen) were studied during and following the large change of the local direct current (DC) potential. Free AA increased markedly during the DC shift, continued to increase during the subsequent 3 min, and returned to control levels at 4-5 min after CSD. PCr decreased by 38% in the first minutes following the DC shift, while ADP increased by 38%. Both returned to normal within a few minutes. ATP, AMP, and energy charge remained constant throughout the experimental period. Glucose decreased by 47% and glycogen by 34% for a few minutes following CSD, while lactate increased by 105% at 2-3 min and by 77% at 4-5 min after CSD. The metabolites returned to control levels at 10 min after CSD. Considering the constant energy charge at all time points during CSD, it is suggested that the AA rise reflects augmented phospholipase activity due to either increased intracellular [Ca2+] or receptor stimulation or both. The possibility that N-methyl-D-aspartate receptors play a role in the release of AA, and that free AA in turn could be part of the mechanism of CSD, is discussed.
Animals↗
Influence of MK-801 on brain extracellular calcium and potassium activities in severe hypoglycemia.
The purpose of the present study was to examine the effect of blockade of N-methyl-D-aspartate (NMDA) receptors on the depolarization associated with severe hypoglycemia, which is commonly preceded by one or a few transient depolarizations reminiscent of cortical spreading depression (CSD). In the cerebral cortices of rats [K+]e and [Ca2+]e were measured with ion-selective microelectrodes. NMDA blockade was achieved by injection of MK801 in doses that block CSD. In control rats, the latency from the time point when blood glucose reached minimal levels to onset of ionic shifts was 33.2 +/- 3.5 min, and [K+]e rose from 3.2 +/- 0.2 to 55 +/- 5 mM. All variables remained unchanged in rats treated with MK801. In another four rats treated with MK801, [Ca2+]e declined from 1.06 +/- 0.22 to 0.12 +/- 0.02 mM. Plasma glucose measurements indicated that the cortex depolarized at a plasma glucose concentration between 0.7 and 0.8 mM, i.e., within a narrow range, suggesting a threshold phenomenon. In conclusion, activation of NMDA receptors seems of minor importance for hypoglycemic depolarization. The ionic transients that precede the persistent hypoglycemic depolarization are probably mediated by mechanisms distinct from those of electrically induced CSD.
Animals↗
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)
Acid-Base Equilibrium↗
Hemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymes.
The levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transferase Ya/Yc subunit, UDP-glucuronosyltransferase isoenzyme (UDPGTr-2), NADPH-cytochrome P450 oxidoreductase, and 5-aminolevulinate synthase. When rats were treated with hemin, together with inducing drug, there was a marked reduction in the induced levels of these mRNAs, with decreases in the range of 55-95%. Basal levels of these mRNAs in the noninduced rat liver were also lowered by hemin administration. Nuclear run-on transcriptional experiments showed that hemin administration substantially lowered both the basal and drug-induced transcriptional activities of the genes for cytochrome P450IIB1/IIB2 and 5-aminolevulinate synthase. In contrast, the mRNA for heme oxygenase was elevated by hemin treatment, whereas the mRNA levels of beta-actin, albumin, and ornithine transcarbamylase, used as controls, were not affected. Treatment of rats with clofibrate resulted in increased levels of mRNA for cytochrome IVA1 and, in addition, those for cytochromes P450IIB1 and P450IIB2. Hemin administration repressed the induction of mRNA levels for cytochromes P450IIB1 and IIB2 but not that for cytochrome P450 IVA1. Additionally, the induction of P450IAI by beta-naphthoflavone was not affected by hemin. The results suggest that heme may negatively control the induction of cytochromes P450IIB1 and IIB2 and other hepatic enzymes by phenobarbitone and phenobarbitone-like drugs and perhaps play a role in regulating drug metabolism. There is, however, no evidence at present as to whether heme has a direct role in such a mechanism or whether injected hemin promotes a secondary response.
5-Aminolevulinate Synthetase↗
Heme may not be a positive regulator of cytochrome-P450 gene expression.
It has been proposed that transcription of cytochrome-P450 genes is positively regulated by heme, the prosthetic group of cytochrome-P450 proteins. We have investigated this proposal in rats treated with succinylacetone, a known specific inhibitor of the heme biosynthetic pathway. While 2-allyl-2-isopropylacetamide, phenobarbitone, dexamethasone, beta-naphthoflavone and clofibrate induced specific cytochrome-P450-mRNA species in rat liver, the levels of these induced mRNAs were not affected by succinylacetone administration. Synthesis of the first enzyme of the heme biosynthetic pathway, 5-aminolevulinate synthase, is known to be regulated by the end-product heme, with heme inhibiting 5-aminolevulinate-synthase-gene transcription. Hepatic 5-aminolevulinate-synthase mRNA was induced by drugs and the level increased further by succinylacetone. Furthermore, treatment of rats with succinylacetone alone resulted in elevated levels of 5-aminolevulinate-synthase mRNA but did not affect cytochrome-P450-mRNA levels. The results show that while lowered heme levels lead to an increase in 5-aminolevulinate-synthase-mRNA synthesis there is no effect on cytochrome-P450-mRNA levels, implying that heme is not required for the cytochrome-P450-gene transcription.
5-Aminolevulinate Synthetase↗
Seizure-induced damage to substantia nigra and globus pallidus is accompanied by pronounced intra- and extracellular acidosis.
Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl[2-14C]oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the "composite" tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Brain acidosis in experimental pneumococcal meningitis.
Purulent meningitis is a serious disease that often has a lethal outcome or gives lasting complications due to brain damage. The processes causing brain dysfunction or damage are still not uncovered nor are the reasons for the characteristic increase of CSF lactate, or the decrease of glucose levels and of pH. We studied rabbits with experimentally induced purulent meningitis (Streptococcus pneumoniae). Ten hours after the inoculation into cisterna magna the rabbits developed symptoms of meningitis, with stiffness of the neck, tachypnea, and fever. The CSF level of lactate and the number of leukocytes were significantly increased and the glucose level was decreased. Brain interstitial pH, as measured by ion selective microelectrodes, was significantly decreased from the normal level of 7.4 to 6.9. The levels of energy metabolites in brain cortex, including glucose, were not different between controls and infected animals, and the lactate level was not elevated more than could have been explained by passive diffusion from the CSF. This shows that the brain tissue is not the source of CSF lactate nor the sink for glucose in CSF. The marked acidification of brain interstitial space and CSF demonstrates that purulent meningitis causes a significant disturbance of brain ion homeostasis that could be, at least in part, responsible for the brain dysfunction. We suggest that activated leukocytes consume CSF glucose and produce lactic acid and secrete protons, which causes the CSF and interstitial acidosis.
Acidosis↗
Sequence of a chicken phenobarbital-inducible cytochrome P450 cDNA: regulation of two P450 mRNAs transcribed from different genes.
The nucleic acid and derived amino acid sequences of a chicken phenobarbital-inducible cytochrome P450 cDNA clone, pCHP7, are presented. The amino acid sequence shares 92% identity with that of a previously characterized chicken cytochrome P450 cDNA clone, pCHP3. The two clones, pCHP7 and pCHP3, represent two distinct mRNAs of 2.2 and 3.5 kb and appear to be transcribed from separate cytochrome P450 genes. Sequence comparisons with P450s from mammalian species indicate that the chicken P450s are most closely related to the IIC subfamily. According to the cytochrome P450 nomenclature (Nebert et al., 1989), the chicken P450 gene encoding the 3.5-kb mRNA is termed P450IIF1 and the P450 gene encoding the 2.2-kb mRNA is designated P450IIF2. When chick embryos were treated with 2-allyl-2-isopropylacetamide, the levels of the 3.5- and 2.2-kb P450 mRNAs in liver were elevated maximally by about 100-fold, while phenobarbital treatment resulted in a maximal increase of about 50-fold. These increases in mRNA levels were accompanied by a less than sixfold increase in the corresponding gene transcription rates. The results indicate that the increase in the amount of these two mRNAs is due to both transcriptional activation of the P450 genes and to a marked post-transcriptional mechanism. By contrast, the drug-induced hepatic mRNA levels for 5-aminolevulinate synthase, the rate-controlling enzyme of the heme biosynthetic pathway, could be accounted for predominantly by activation of gene transcription. A close correlation was observed between the time courses of hepatic mRNA accumulation for cytochrome P450 and 5-aminolevulilnate synthase following drug treatment of chick embryos. In adult hens it was demonstrated that a tissue-specific drug induction of cytochrome P450 mRNAs occurred with levels being substantially elevated in the liver, kidney, and small intestine. The mRNA for 5-aminolevulinate synthase was also drug-induced in the same tissue-specific fashion. The results are compatible with the gene for 5-aminolevulinate synthase being activated in response to an increased cytochrome P450 heme requirement.
Amino Acid Sequence↗
Regional cerebral blood flow and glucose utilization during hypocapnia and adenosine-induced hypotension in the rat.
Hypocapnia and induced hypotension have been claimed by some to cause cerebral hypoxia because of insufficient perfusion. Regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCMRglc) were measured simultaneously in the same animal subjected to hypocapnia or hypocapnia combined with induced arterial hypotension. The rCMRglc was measured with (3H) deoxyglucose and the rCBF with (14C) iodoantipyrine with the use of tissue biopsy methods and scintillation counting. Nineteen male Wistar rats were anesthetized with halothane and artificially ventilated. Anesthesia was maintained with nitrous oxide/oxygen (70:30) and succinylcholine. Six rats were maintained at normocapnia, six rats were ventilated to a PaCO2 of 20 mmHg, and seven animals were ventilated to PaCO2 20 mmHg combined with arterial hypotension of 50 mmHg (mean blood pressure) induced by infusion of adenosine. Although hypocapnia alone did not cause a statistically significant decrease of rCBF except in hippocampus, hypocapnia combined with hypotension resulted in a significant reduction of rCBF in four of seven regions when compared with hypocapnia alone; rCMRglc values were unchanged during hypocapnia. However, the addition of hypotension induced by adenosine led to a significant decline of glucose utilization in five of seven brain regions. In the present study the authors observed no increase of regional glucose utilization and hence no signs of cerebral ischemia during hypocapnia alone or combined with hypotension induced by adenosine.
Adenosine↗
Hypocapnia prevents the decrease in regional cerebral metabolism during isoflurane-induced hypotension.
In neurologic surgery, induced hypotension is often used while the patient is hypocapnic. We investigated, by tissue biopsy methods and scintillation counting, the regional cerebral glucose utilization (rCMRglc) and blood flow (rCBF) in rats subjected to hypocapnia alone and in combination with hypotension. Anesthesia was maintained with 1.0% isoflurane in nitrous oxide/oxygen. Seven rats were maintained at PaCO2 of 40 mm Hg, six rats were ventilated to PaCO2 of 20 mm Hg, and six animals to PaCO2 of 20 mm Hg in combination with arterial hypotension of 50 mm Hg induced by isoflurane 2.5-3.5%. During hypocapnia, rCMRglc tended to increase in all regions, but the increase was statistically insignificant; rCBF was reduced uniformly by 40%. During combined hypocapnia/hypotension, rCMRglc was unaltered when compared to hypocapnia; compared to normocapnia, increases were seen in hippocampus and cerebellum. During hypocapnia/hypotension, rCBF was unaltered in cortical areas, while increases were seen in all subcortical areas compared to hypocapnia. Regional values of the ratio of rCBF/rCMRglc indicated that during hypocapnia and hypotension induced by isoflurane in nitrous oxide/oxygen, the individual brain areas were perfused according to their metabolic needs. It is suggested that hypocapnia may prevent the decrease in rCMRglc, which is usually observed during deep isoflurane anesthesia.
Journal Article↗
Ion distributions in brain during ischemia.
The function of the central nervous system-and other organs-depends upon preservation of ionic gradients across cell membranes. In nervous tissue, the ion gradients are especially important since generation of action potentials and synaptic processes relies on transfer of ions across the plasma membrane. This report describes the fact that anoxia profoundly changes the brain interstitial ion milieu. Impaired ATP regeneration starts the chain of events that cause a breakdown of ion homeostasis. The pronounced ionic changes are not caused by impaired ion pumping but rather by opening of ion channels-probably most importantly via release of transmitter substances. Despite the severity of the ionic changes, the brain interstitial ion environment is readily normalized after the anoxic episode. The ionic disturbances are not the cause of the functional deficits encountered in anoxia but are probably of significance in the irreversible neuronal damage evolving after anoxia.
Journal Article↗
Effect of haem on cytochrome P-450 synthesis.
1. The expression of the phenobarbital-inducible cytochrome P-450 mRNA species (P-450 IIB1 and IIB2) were investigated in different tissues of rats following treatment with 2-allyl-2-isopropylacetamide. 2. The mRNAs were detected as a single 2.1 kb mRNA species by Northern blot analysis. These mRNAs were readily detected in liver, lung and kidney but were not detected in testis, brain or erythroid tissue. 3. When rats were administered 2-allyl-2-isopropylacetamide, cytochrome P-450 levels were elevated specifically in the liver and kidney but remained undetectable in testis, brain and erythroid spleen. Thus these cytochrome P-450 mRNAs are expressed and induced by drug in a tissue-specific fashion. Levels of mRNA for 5-aminolaevulinate synthase, the rate controlling enzyme of haem biosynthesis, were also induced by drug in a similar tissue-specific fashion. 4. The proposal that haem is required for the transcription of cytochrome P-450 IIB1/IIB2 and other cytochrome P-450 genes was investigated in rat liver using succinylacetone, a specific inhibitor of the haem biosynthetic pathway. 5. While 2-allyl-2-isopropylacetamide induced levels of cytochrome P-450 IIB1/IIB2 mRNAs, succinylacetone administration did not affect this induction. However, succinylacetone substantially elevated both basal and drug-induced levels of mRNA for 5-aminolaevulinate synthase. 6. Since 5-aminolaevulinate synthase mRNA synthesis is inhibited by the end-product haem, the results show that lowered haem levels do not affect cytochrome P-450 gene transcription. The work does not provide evidence for the suggestion that haem is required for cytochrome P-450 gene transcription.
5-Aminolevulinate Synthetase↗
Determination of brain interstitial concentrations by microdialysis.
Microdialysis is an extensively used technique for the study of solutes in brain interstitial space. The method is based on collection of substances by diffusion across a dialysis membrane positioned in the brain. The outflow concentration reflects the interstitial concentration of the substance of interest, but the relationship between these two entities is at present unclear. So far, most evaluations have been based solely on calibrations in saline. This procedure is misleading, because the ease by which molecules in saline diffuse into the probe is different from that of tissue. We describe here a mathematical analysis of mass transport into the dialysis probe in tissue based on diffusion equations in complex media. The main finding is that diffusion characteristics of a given substance have to be included in the formula. These include the tortuosity factor (lambda) and the extracellular volume fraction (alpha). We have substantiated this by studies in a well-defined complex medium (red blood cell suspensions) as well as in brain. We conclude that the traditional calculation procedure results in interstitial concentrations that are too low by a factor of lambda 2/alpha for a given compound.
Animals↗
Regulation of genes associated with drug metabolism.
Exposure of animals to foreign chemicals results in the induction of many enzymes. The mitochondrial enzyme 5-aminolaevulinate synthase (ALV-S) is induced to supply haem for cytochrome P-450 (P-450) enzymes, the key proteins in drug detoxification. The drugs phenobarbital and 2-allyl-2-isopropylacetamide (AIA), although structurally different, elevate levels of ALV-S and a specific class of P-450s, the phenobarbital-inducible P-450s. Synthesis of ALV-S is negatively controlled by the end-product haem and it is proposed that drugs induce P-450 apoprotein which sequesters haem. Studies at the mRNA level show that ALV-S and P-450 are drug induced in a highly tissue-specific fashion and that haem represses mRNA levels in all but erythroid tissues. In liver, drugs activate ALV-S gene transcription and haem represses, but this mechanism does not operate in erythroid cells. Studies on the drug-induction mechanism of phenobarbital-inducible P-450s in chick embryo liver show that increased mRNA levels result from P-450 gene activation together with a significant post-transcriptional mechanism.
5-Aminolevulinate Synthetase↗
Recovery of ion homeostasis and electrical activity in brain after ischemia does not require glucose.
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Animals↗
Spreading depression is not associated with neuronal injury in the normal brain.
This study was performed in order to evaluate whether waves of spreading depression (SD) induces irreversible neuronal injury. SD was elicited by topical application of 3 M KCl to the exposed cortex for 4-5 h and the resulting change of the cortical electrical potential showing the occurrence of SD, was recorded by glass microelectrodes. Histological examination of cerebral cortex revealed no signs of neuronal injury outside the area of KCl application as examine after 4 days recovery. The results indicate that recurrent waves of SD do not induce irreversible neuronal injury in the otherwise normal rat brain.
Animals↗