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PubMed1999

Potentiation of excitotoxic injury by high concentrations of extracellular reduced glutathione.

Glutathione is present in the central nervous system in millimolar concentrations, and is a predominant intracellular antioxidant and detoxicant. In addition, glutathione is released into the extracellular space via a depolarization-enhanced process. Although the role of extracellular glutathione has not been precisely defined, a growing body of experimental evidence suggests that it has multifaceted electrophysiological effects. At low micromolar concentrations, glutathione depolarizes neurons by binding to its own receptors and modulates glutamatergic excitatory neurotransmission by displacing glutamate from its ionotropic receptors. At higher concentrations, reduced glutathione may increase N-methyl-D-aspartate receptor responses by interacting with its redox sites. In this study, the effect of extracellular glutathione on excitotoxic neuronal injury was quantitatively assessed in murine cortical cell cultures. Neuronal death due to 20-25 h exposure to 6-9 microM N-methyl-D-aspartate was not altered by 10-100 microM reduced glutathione but was markedly enhanced by 300-1000 microM reduced glutathione; kainate neurotoxicity was unaffected. Two related compounds that lack a sulfhydryl group, oxidized glutathione and S-hexylglutathione, had no significant effect on N-methyl-D-aspartate neurotoxicity alone but completely blocked the effect of reduced glutathione. Mercaptoethanol, a sulfhydryl reducing agent that increases N-methyl-D-aspartate receptor responses by interacting with redox sites, increased N-methyl-D-aspartate neurotoxicity to a degree comparable to that of reduced glutathione; this effect was also blocked by equimolar S-hexylglutathione or oxidized glutathione. Addition of reduced glutathione to mercaptoethanol did not further increase N- methyl-D-aspartate-induced neuronal death. These results suggest that release of reduced glutathione from central nervous system cells that are subjected to traumatic or ischemic insults may enhance excitotoxic neuronal loss. Although multiple mechanisms may account for this phenomenon, the high concentrations required suggest that it is at least partly mediated by reduction of N-methyl-D-aspartate receptor redox sites.

Animals↗

PubMed2003

Extracellular amyloid formation and associated pathology in neural grafts.

Amyloid precursor protein (APP) processing and the generation of beta-amyloid peptide (Abeta) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Abeta in the extracellular space is involved in the spread of Abeta pathology, and that extracellular amyloid formation can lead to neurodegeneration.

Alzheimer Disease↗

PubMed2005

Theory for the impact of basal turnover on dopamine clearance kinetics in the rat striatum after medial forebrain bundle stimulation and pressure ejection.

Although microdialysis measurements suggest that extracellular dopamine concentrations in the rat striatum are in the low nanomolar range, some recent voltammetry studies suggest that the concentration may be considerably higher, perhaps in the micromolar range. The presence of such high dopamine levels in the extracellular space has to be rationalized with the rapid, linear clearance of extracellular dopamine observed after electrical stimulation of the medial forebrain bundle. Kinetic analysis of dopamine clearance after evoked release suggests that the basal extracellular dopamine concentration is below the K(M) of dopamine uptake, which is near 0.2 microm. However, dopamine clearance after pressure ejection of dopamine into the rat striatum is slow and non-linear, which may alternatively be a sign that basal dopamine release is only slightly slower than the maximal velocity of dopamine uptake, Vmax. A high basal extracellular dopamine concentration would exist if basal dopamine release were only slightly slower than the Vmax of uptake. This report introduces a new kinetic analysis of dopamine uptake that sheds light on the possible source of the different clearance rates observed following evoked dopamine release and dopamine pressure ejection. Furthermore, the analysis rationalizes the rapid dopamine clearance after evoked release with the possibility that basal extracellular dopamine levels are above the K(M) of the transporter.

Animals↗

PubMed1987

Modulation of spinal cord transmission by changes in extracellular K+ activity and extracellular volume.

The neuronal activity in spinal cord in response to electrical or adequate stimulation of afferent fibres increases extracellular K+ activity. The increase during a stimulation can reach 9-10 mM (so-called ceiling level) and persists for some time even when a stimulation is discontinued. The activation of a neuronal Na-K pump is a limiting factor in stimulation-evoked increase in extracellular K+ activity and in the time course of its recovery to the resting level. Drugs that affect either the neuronal activity (picrotoxin, strychnine, GABA, 5-HT) or activity of Na-K ATPase (oubain, naloxone, morphine, enkephalins) substantially change the K+ transience. Repetitive electrical stimulation of low threshold cutaneous afferents at frequency 1-100 Hz induced transient shrinkage of extracellular space in spinal dorsal horns by 5-75%. The increase in extracellular K+ activity depolarizes the membranes of neurones, glial cells, and primary afferent fibres and may eventually lead to either facilitation or inhibition of synaptic transmission. It is also suggested that the transient poststimulation changes in extracellular volume may alter synaptic potency in spinal cord.

Animals↗

PubMed1994

Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis.

We report the first study of carbamazepine and carbamazepine-10,11-epoxide concentrations determined by using intracerebral microdialysis in three patients undergoing depth electrode studies for the evaluation of medically intractable epilepsy. Very small microdialysis catheters, affixed to and inserted with the depth electrodes, sampled drug concentration in the extracellular environment. We perfused artificial extracellular fluid continuously, and varied the perfusion rate to permit estimation of the absolute drug concentration in the extracellular space. Serum samples were obtained simultaneously. The relation between dialysate and extracellular concentration (recovery fraction) depended, in vivo but not in vitro, on the relative lipophilicity of the compounds, suggesting that diffusion of the drug within the brain is a major determinant of microdialysate drug concentration. When this is taken into account, the steady-state extracellular concentrations of these compounds closely mirror their unbound serum concentrations.

Brain Chemistry↗

PubMed1980

"Exaggerated" natriuresis in experimental hypertension and the role of the natriuretic factor.

In rabbits with experimental ischaemic cerebral hypertension the role of the natriuretic factor in the genesis of the phenomenon of "exaggerated" natriuresis after extracellular space expansion was studied. In control animals an expansion of the extracellular fluid was followed by an elevation of the natriuretic factor in blood, whereas in hypertensive rabbits the phenomenon did not appear. Besides, in hypertensive rabbits the urinary excretion and the clearance of the natriuretic factor were considerably higher than in the control animals. In the genesis of exaggerated natriuresis in hypertension a certain role is doubtlessly played by the natriuretic factor.

Animals↗

PubMed1994

[Anatomical and functional characteristics of the myocardial interstitial space].

The extracellular matrix plays an important role in biological processes, for example cellular adhesion, proliferation, migration and differentiation. Many of the cell-cell and cell-matrix interactions are mediated by extracellular matrix components and by their respective membrane receptors. Important pathophysiological processes occur through these interactions of which ontogenesis tissue differentiation and reconstruction, many inflammatory and immunological events and metastatic processes and invasion. The myocardium is made of muscular, vascular and connective components that exist in a state of equilibrium based on their relative proportions, integral structures, and on their physical and chemical characteristics. The Authors have described molecular events that lead to the organization of the cardiac tissue in physiological conditions and to its reorganization in pathological situation. Furthermore they have evaluated the role of fibronectin, a glycoprotein of the extracellular matrix in the initial phase of cardiac ischemia.

Extracellular Space↗

PubMed1990

A comprehensive model of the dynamic exchange processes during hemodialysis.

The present model for the mathematical description of exchange processes during hemodialysis includes submodels for potassium, sodium, chloride, acetate, acid-base status (with CO2, bicarbonate and H(+)-ions), water distribution, oxygen, ventilation, and the uremic catabolites urea, creatinine, and vitamin B12. For potassium, sodium and urea a 2-compartment model is used consisting of the extra- and the intracellular space. For chloride, creatinine and vitamin B12 a 3-compartment model is necessary. For the description of acetate kinetics a 1-compartment model consisting of the extracellular space is sufficient. For description of the acid-base balance the model includes three submodels for CO2, bicarbonate, and hydrogen ions. All submodels are made of eight compartments, namely the intracellular and the interstitial space as well as six spaces for the blood. The three submodels are coupled to each other by the chemical reaction of CO2 to HCO3- and a H(+)-ion. Besides this reaction the diffusive exchange between the compartments, the convective transport with the blood and the elimination through the dialyzer and the lung for the molecules and ions are considered. Because of the strong buffer capacity of plasma and intracellular proteins, the functional compartments for hydrogen ions are larger than the anatomical spaces. Also the influence of extracellular pH on the electrolyte distribution at the cell membrane has been considered. With this model, which will be adapted to the patient by more than 45 individual parameters, the mass transfer and the course of concentrations during hemodialysis therapy can be reproduced adequately. Further on the values of some unknown parameters, such as the metabolic rate for acetate in the organism, can be estimated by varying the parameters systematically for several runs of the computer simulation until the simulation results are optimally fitted to measured data.

Acid-Base Equilibrium↗

PubMed1983

Non-radioisotopic estimate of extracellular volume during isotonic expansion in anuric dogs.

In six anuric dogs infused in two steps with isonatremic (= having the same sodium concentration as each dog's initial extracellular space) sodium chloride solutions, stable chloride space was computed by mass conservation and was compared to radiosulphate space. There was close agreement between estimates of preinfusion extracellular volume by radiosulphate and stable chloride spaces. Computed increases in radiosulphate and stable chloride spaces agreed with the infused volumes in each step.

Animals↗

PubMed1985

Extracellular carbonic anhydrase of skeletal muscle associated with the sarcolemma.

We report here 1) the synthesis and properties of a new macromolecular carbonic anhydrase inhibitor, Prontosil-dextran, 2) its application to determine the localization of a previously described extracellular carbonic anhydrase in skeletal muscle, and 3) the application of a recently published histochemical technique using dansylsulfonamide to the same problem. Stable macromolecular inhibitors of molecular weights of 5,000, 100,000 and 1,000,000 were produced by covalently coupling the sulfonamide Prontosil to dextrans. Their inhibition constants towards bovine carbonic anhydrase II are 1-2 X 10(-7) M. The Prontosil-dextrans, PD 5,000, PD 100,000, and PD 1,000,000, were used in studies of the washout of H14CO3-) from the perfused rabbit hindlimb. This washout is slow due to the presence of an extracellular carbonic anhydrase and can be markedly accelerated by PD 5,000 but not by PD 100,000 and PD 1,000,000. Since PD 5,000 is accessible to the entire extracellular space and PD 100,000 and PD 1,000,000 are confined to the intravascular space, we conclude that the extracellular carbonic anhydrase of skeletal muscle is located in the interstitium. The histochemical studies show a strong staining of the sarcolemma of the muscle fibers with high oxidative capacity. It appears likely, therefore, that the extracellular carbonic anhydrase of skeletal muscle is associated with muscle plasma membranes with its active site directed toward the interstitial space.

Animals↗

PubMed2003

High-throughput classification of yeast mutants for functional genomics using metabolic footprinting.

Many technologies have been developed to help explain the function of genes discovered by systematic genome sequencing. At present, transcriptome and proteome studies dominate large-scale functional analysis strategies. Yet the metabolome, because it is 'downstream', should show greater effects of genetic or physiological changes and thus should be much closer to the phenotype of the organism. We earlier presented a functional analysis strategy that used metabolic fingerprinting to reveal the phenotype of silent mutations of yeast genes. However, this is difficult to scale up for high-throughput screening. Here we present an alternative that has the required throughput (2 min per sample). This 'metabolic footprinting' approach recognizes the significance of 'overflow metabolism' in appropriate media. Measuring intracellular metabolites is time-consuming and subject to technical difficulties caused by the rapid turnover of intracellular metabolites and the need to quench metabolism and separate metabolites from the extracellular space. We therefore focused instead on direct, noninvasive, mass spectrometric monitoring of extracellular metabolites in spent culture medium. Metabolic footprinting can distinguish between different physiological states of wild-type yeast and between yeast single-gene deletion mutants even from related areas of metabolism. By using appropriate clustering and machine learning techniques, the latter based on genetic programming, we show that metabolic footprinting is an effective method to classify 'unknown' mutants by genetic defect.

Cells, Cultured↗

PubMed1998

Regulation of extracellular dopamine by the norepinephrine transporter.

There is growing evidence of an interaction between dopamine and norepinephrine. To test the hypothesis that norepinephrine terminals are involved in the uptake and removal of dopamine from the extracellular space, the norepinephrine uptake blocker desmethylimipramine (DMI) was infused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrations of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic administration of haloperidol and the local infusion of DMI produced an augmented increase in extracellular dopamine in the cortex compared with the increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediated dopamine release produced by haloperidol and blockade of the norepinephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the alpha2-antagonist idazoxan also increased the extracellular concentrations of dopamine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concentrations of norepinephrine produced by these drugs, an increase in dopamine also was observed in lesioned rats that were depleted of norepinephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned controls. These results suggest that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.

Adrenergic alpha-Antagonists↗

PubMed1997

A new action of parathyroid hormone. receptor-mediated stimulation of extracellular acidification in human osteoblast-like SaOS-2 cells.

The major physiological function of parathyroid hormone (PTH) is the maintenance of Ca2+/Pi homeostasis via the parathyroid hormone/parathyroid hormone-related protein receptor (PTHR) in kidney and bone. An important consequence of PTHR activation in bone is enhanced local acidification of the extracellular space. Agonist activation of some seven transmembrane-domain receptors increases the extracellular acidification rate (ECAR). We utilized microphysiometry to investigate PTH-stimulated, receptor-mediated increases in ECAR in human osteoblast-like SaOS-2 cells. PTH-(1-34) elicited a large, acute, dose-dependent increase in ECAR with an EC50 of about 2 nM. The PTH-induced increase in ECAR was specific to cells expressing the PTHR and was inhibited by PTHR antagonists. Rapid, partial, homologous desensitization of the PTH-induced increase in ECAR was observed. Incubation of SaOS-2 cells with 8-bromo-cyclic AMP neither mimicked nor abrogated the PTH effect, and PTH stimulated an acute increase in ECAR in cAMP-resistant SaOS-2 Ca#4A cells. Stimulation of ECAR by PTH was independent of transient increases in cytosolic free calcium. Both inhibition and down-regulation of PKC reduced the PTH-induced increase in ECAR. Inhibition of Na+/H+ exchange did not affect the PTH-induced ECAR response. We conclude that PTH caused a receptor-mediated, concentration-dependent, increase in ECAR, which was not dependent on the cAMP/PKA signaling pathway or the Na+/H+ exchanger but involved the action of PKC. Thus, acid production in bone, a physiologically important action of PTH, is not confined to osteoclasts as previously considered but is also mediated by osteoblasts.

Cell Line↗

PubMed1988

Morphology of the isolated rat hindquarter preparation: tissue preservation, perfusion heterogeneity and a note on the effect of fixative osmolality.

The isolated rat hindquarter preparation often used for physiological studies was subjected to morphological examination. A two-hour perfusion with balanced oxygenated dextran solution was followed by perfusion fixation with aldehydes. Fixation was performed at isogravimetry when an isotonic fixative was used (2.5% glutaraldehyde in 0.05 M Na cacodylate + 4% dextran 70). Muscle specimens were prepared for light and electron microscopy. Most muscle tissue was well perfused but a limited tissue volume could retain blood after the perfusion period. Within perfused tissue the perfusion result varied macroscopically with some regions apparently not being reached by fixative. Non-fixed tissue was estimated to amount to maximally one fourth of the total tissue mass. Also within macroscopically well-fixed tissue the microscopy indicated varying patency of perfused capillaries. Thus a marked perfusion flow heterogeneity prevailed in the fixed specimens which is compatible with earlier functional findings of a 50% reduction of capillary surface area during isogravimetric fixation. The possible relation with prefixation flow heterogeneity in the vasodilated preparation is discussed. There were no obvious alterations of endothelial ultrastructure after prolonged artificial perfusion. Isogravimetrically fixed muscle had narrow extracellular spaces which were evidently compressed further after use of absorbing hyperosmolar fixative. Extracellular expansion and intracellular oedema followed after hypo-osmolar fixation. Muscle cells often exhibited insufficient mitochondrial fixation, probably as a result of tissue hypoxia.

Aldehydes↗

PubMed1982

Effects of extracellular potassium accumulation and sodium pump activation on automatic canine Purkinje fibres.

1. Double barrel potassium-sensitive micro-electrodes were used to measure fluctuations in extracellular potassium ion concentration in large automatic canine Purkinje fibres.2. Slow accumulations of potassium were seen in the extracellular space during prolonged beating. Following cessation of prolonged beating, a depletion of extracellular potassium ions was noted.3. The time course of these slow changes in extracellular potassium concentration were shown to be a function of the diffusion properties of the preparation, and the rate and degree of activation of the sodium pump.4. Action potential duration and maximum diastolic potential were simultaneously monitored during and after these periods of rapid stimulation, using conventional intracellular micro-electrodes.5. Initial depolarization and later hyperpolarization of the maximum diastolic potential appeared to occur as a direct result of changes in extracellular potassium concentration and level of pump activation induced by the sudden and prolonged alteration in stimulus rate.6. Following prolonged stimulation, dramatic changes in the automatic beating rate were correlated with changes in extracellular potassium and pump rate, and their effects on the maximum diastolic potential and other parameters of the diastolic potential depolarization.7. For some locations of the potassium-sensitive electrode tip, large fluctuations in extracellular potassium were seen during single beats. Alterations in action potential duration during abrupt rate changes appear to derive in part from modulation by these extracellular potassium concentration fluctuations altering net membrane currents. Slower shifts in action potential duration appear correlated to the degree of sodium pump activation.

Action Potentials↗

PubMed2005

Transport of extracellular l-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production.

In cultured endothelial cells, 70-95% of extracellular l-arginine uptake has been attributed to the cationic amino acid transporter-1 protein (CAT-1). We tested the hypothesis that extracellular l-arginine entry into endothelial cells via CAT-1 plays a crucial role in endothelial nitric oxide (NO) production during in vivo conditions. Using l-lysine, the preferred amino acid transported by CAT-1, we competitively inhibited extracellular l-arginine transport into endothelial cells during conditions of NaCl hyperosmolarity, low oxygen, and flow increase. Our prior studies indicate that each of these perturbations causes NO-dependent vasodilation. The perivascular NO concentration ([NO]) and blood flow were determined in the in vivo rat intestinal microvasculature. Suppression of extracellular l-arginine transport significantly and strongly inhibited increases in vascular [NO] and intestinal blood flow during NaCl hyperosmolarity, lowered oxygen tension, and increased flow. These results suggest that l-arginine from the extracellular space is accumulated by CAT-1. When CAT-1-mediated transport of extracellular l-arginine into endothelial cells was suppressed, the endothelial cell NO response to a wide range of physiological stimuli was strongly depressed.

Animals↗

PubMed1996

Hypoxia-reoxygenation increases O2-. efflux which injures endothelial cells by an extracellular mechanism.

The mechanisms by which superoxide anion (O2-.) injures reoxygenated vascular cells are not clearly understood. We hypothesized that O2-. formed in an intracellular compartment during reoxygenation may egress through plasmalemmal anion channels and mediate injury from an extracellular site. Bovine pulmonary artery endothelial cells (EC) kept hypoxic for 48 h had increased release of preloaded 51Cr upon reoxygenation. Evidence for an extracellular site of injury was the following. First, decreasing extracellular O2-. levels (measured by cytochrome c reduction) with the anion channel blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) leads to decreased 51Cr leak. In contrast to its effect on extracellular O2-., DIDS increased intracellular O2-. levels (measured by nitroblue tetrazolium reduction) following reoxygenation. Second, treatment with exogenous superoxide dismutase (SOD), while having no significant effect on intracellular O2-. levels, also decreased 51Cr leak. Furthermore, cotreatment of EC with DIDS did not abrogate the protective effects of exogenous SOD, suggesting that SOD decreased injury by decreasing extracellular and not intracellular O2-. Finally, exposure of EC to extracellularly generated O2-. (xanthine oxidase/hypoxanthine system) caused injury, which was decreased by SOD but not by blockade of O2-. entry with DIDS. The mechanism by which O2-. injures EC may involve generation of .OH by surface-associated iron, since iron chelators and .OH scavengers of varying membrane permeability all decreased 51Cr release to a similar extent. Furthermore, the iron chelators and .OH scavengers also decreased EC 51Cr leak following exposure to exogenous xanthine oxidase/hypoxanthine but not following exposure to a O2(-.)-independent agent (A23187). We conclude that hypoxia-reoxygenation injures EC in a manner that is at least in part dependent on the efflux of O2-. into the extracellular space. Endogenous and exogenous strategies for protection against reoxygenation injury must target extracellular O2-. as a potentially harmful species.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1975

Hypertrophy of intestinal smooth muscle.

Proximal to an experimental stenosis of the small intestine of rats and guinea-pigs a remarkable hypertrophy of the muscle coat develops 3-5 weeks after the operation. There is no increase in the length of the intestine but an overall increase in volume of the muscularis externa up to 10 times. This increase is accounted for by an increase in size and in number (by mitosis) of smooth muscle cells of both the longitudinal and circular layers. Bundles of newly-formed smooth cells appear in the serosa and are circularly arranged. In the hypertrophic smooth muscle cells of the circular layer the ratio of surface to volume is 0.80 (0.80 mum2 of cell surface for every mum3 of cell volume) as against 1.4 in the control muscle. The hypertrophic muscle cells have a highly developed sarcoplasmic reticulum and show a large number of nexuses. The density of innervation (number of axons per given number of smooth muscle cells) is smaller than in controls. Few collagen fibrils are visible in the extracellular space.

Animals↗