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PubMed1983

Spontaneous epileptiform activity of CA1 hippocampal neurons in low extracellular calcium solutions.

Lowering extracellular [Ca2+] in rat hippocampal slices induces spontaneous epileptiform activity in area CA1, which is characterized by rhythmic burst firing of CA1 neurons and by prolonged negative potential shifts at the pyramidal cell body layer. This activity is accompanied by transient decreases of [Na+] and increases of [K+] in the extracellular space. In spite of the complete blockade of synaptic transmission, the wave of epileptiform activity propagates across area CA1. These findings suggest, that non-synaptic mechanisms may play a role in the generation and spread of epileptiform activity in the mammalian CNS.

Animals↗
PubMed2000

N-desethylamiodarone modulates intracellular calcium concentration in endothelial cells.

The main in-vivo metabolite of amiodarone, N-desethylamiodarone (DEAM), possesses clinically relevant class-II antiarrhythmic and vasodilator activities. Vasodilation by DEAM is endothelium dependent and involves a sustained and biphasic increase in cytosolic free Ca2+ concentration ([Ca2+]i). The aims of this study were to explore the mechanisms mediating the DEAM-induced increase in [Ca2+]i in endothelial cells and to determine whether this increase in [Ca2+]i was associated with altered cell proliferation. Cultured bovine aortic endothelial cells were loaded with the Ca2+-sensitive fluorescent dye Fura-2/AM, and [Ca2+]i measured spectrofluorimetrically. DEAM increased [Ca2+]i concentration dependently (EC50 approximately 6 microM) both in the presence and absence of extracellular Ca2+. In the presence of extracellular Ca2+, the response of [Ca2+]i to DEAM (10 microM) consisted of an initial rise to a plateau followed by a second increase to micromolar levels. The initial plateau was reduced by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (200 nM) and by the antioxidant ascorbic acid (100 microM). The initial rate of rise in [Ca2+]i was decreased by blocking mitochondrial Ca2+ release with cyclosporine A (1 microM). Under Ca2+-free conditions, the response of [Ca2+]i to DEAM (10 microM) was also biphasic, consisting of an initial transient peak and a second slow increase. When extracellular Ca2+ was restored, [Ca2+]i rose to micromolar concentrations. The initial peak was abolished by thapsigargin, but not altered by ascorbic acid or cyclosporine A. Both the second [Ca2+]i increase and that due to restoring extracellular Ca2+ were reduced by ascorbic acid but not affected by thapsigargin or cyclosporine A. The DEAM-induced generation of free radicals and sustained increase in [Ca2+]i might alter cell proliferation and endothelial cell proliferation was indeed concentration-dependently inhibited by DEAM (IC50 approximately 2.5 microM). In conclusion, the DEAM-induced [Ca2+]i increase in endothelial cells is due to Ca2+ influx from the extracellular space and to Ca2+ release from endoplasmic reticulum and mitochondria and involves enhanced generation of free radicals.

Amiodarone↗
PubMed1993

Effects of extracellular magnesium manipulation on reperfusion-induced arrhythmias and myocardial ion shifts in isolated ischemic reperfused rat hearts.

Isolated rat hearts were subjected to global ischemia followed by reperfusion, and a reduction in the incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia was brought about by increasing the extracellular Mg concentration in the perfusion buffer. Thus the incidence of ventricular fibrillation was reduced from its control value of 100% in 1.2 mM Mg to 83% by 2.4 mM Mg (P = N.S.), to 42% by 3.6 mM Mg (P < .05), to 17% by 4.8 mM Mg (P < .001) and to 17% by 9.6 mM Mg (P < .001). The corresponding values for ventricular tachycardia were 100% (control, 1.2 mM Mg) vs. 92% (P = N.S.), 50% (P < .05), 25% (P < .01) and 25% (P < .01), respectively. In further studies, extracellular Ca was reduced by 50% (1.2 mM) in the perfusion buffer just before ischemia and during reperfusion. The incidence of ventricular fibrillation was reduced from its control value of 83% in 1.2 mM Mg to 75% by 1.8 mM Mg (P = N.S.), to 33% by 2.4 mM Mg (P < .05), to 17% by 3.6 mM Mg (P < .01) and to 8% by 4.8 mM Mg (P < .01). The incidence of ventricular tachycardia followed the same pattern. Myocardial Na, K, Ca and Mg were measured by atomic absorption spectrophotometer after the removal of ions from the extracellular space. In controls, 30 min of ischemia resulted in 3- and 4-fold accumulation of myocardial Na and Ca, respectively, and during reperfusion these values were similar to the values for 30-min ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Measured muscle sodium content in biopsy specimens is a reflection of true intracellular content.

Determined on the basis of small skeletal muscle biopsies, muscle sodium content has a very high coefficient of variation. Furthermore, at least some of the measured sodium must originate from the extracellular space. In order to assess the applicability of the measurement of intracellular sodium on small muscle biopsy specimens, the measured sodium content was related to the content of dry solids in 25 muscle biopsy samples, and compared with the theoretical content of sodium with varying extra- and intracellular water content in biopsy samples. Four of the 25 measurements were clearly outliers. Disregarding these outliers, it was found that muscle sodium content varied with intracellular water content, whereas the theoretical effect of addition of extracellular water could not account for the observed values. The difference depended upon the specified conditions, but the slope of the theoretical regression line (-25.92 mmol x (kg dry weight)(-1) x %(-1), which was closest to the observed slope, -8.55 mmol x (kg dry weight)(-1) x %(-1), differed substantially (p < 0.0001). No association was found between the primarily intracellular ions muscle potassium and muscle magnesium on the one hand and either muscle sodium or muscle water content on the other. The measured sodium content in muscle biopsy specimens, which are freeze-dried and dissected, seems to reflect the true intracellular sodium content to some extent. The total content of sodium seems to be closely related to the content of water within the skeletal muscle cells.

Biopsy↗
PubMed2005

Generation of free radicals during decomposition of hydroperoxide in the presence of myeloperoxidase or activated neutrophils.

It was shown with the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone that myeloperoxidase (MPO) in the presence of its substrates H2O2 and Cl- as well as activated neutrophils destroy tert-butyl hydroperoxide producing two adducts of O-centered radicals which were identified as peroxyl and alcoxyl radicals. Inhibitory analysis performed with traps of hypochlorite (taurine and methionine), free radical scavengers (2,6-di-tret-butyl-4-methylphenol and mannitol), and MPO inhibitors (salicylhydroxamic acid and 4-aminobenzoic acid hydrazide) revealed that the destruction of the hydroperoxide group in the presence of isolated MPO or activated neutrophils was directly caused by the activity of MPO: some radical intermediates appeared as a result of the chlorination cycle of MPO at the stage of hypochlorite generation, whereas the other radicals were produced independently of hypochlorite, presumably with involvement of the peroxidase cycle of MPO. The data suggest that the activated neutrophils located in the inflammatory foci and secreting MPO into the extracellular space can convert hydroperoxides into free radicals initiating lipid peroxidation and other free radical reactions and, thus, promoting destruction of protein-lipid complexes (biological membranes, blood lipoproteins, etc.).

Catalysis↗
PubMed2005

Detection of beta-endorphin in the cerebrospinal fluid after intrastriatal microinjection into the rat brain.

We have investigated to what extent microinjected beta-endorphin could migrate from the rat brain parenchyma into the CSF compartment. Exogenous rat beta-endorphin (0.1 nmol) was microinjected into the left striatum 1 mm from the lateral ventricle in anesthetized male rats. CSF samples were collected at different time points up to 2 h post-injection from a catheter affixed to the atlanto-occipital membrane of the cisterna magna. Radioimmunoassay and mass spectrometry were performed on the CSF samples, and brain sections were immunostained for beta-endorphin and mu-opioid receptors. The beta-endorphin injected rats showed a marked increase in beta-endorphin immunoreactive (IR) material in the CSF, with a peak at 30-45 min post-injection, and this beta-endorphin-IR material existed mainly as the intact beta-endorphin peptide. The immunohistochemistry results revealed the appearance of distinct beta-endorphin-IR cell bodies in the globus pallidus and the bed nucleus of stria terminalis supracapsular part, regions distant from the injection site, at 2 h post-injection of exogenous beta-endorphin. The beta-endorphin-IR in several of the globus pallidus cell bodies colocalized with the mu-opioid receptor-IR at the cell surface. These findings show that upon delivery of synthetic beta-endorphin, there is a significant intracerebral spread of the injected peptide, reaching regions far from the site of injection via diffusion in the extracellular space and flow in the cerebrospinal fluid. This may be of relevance when interpreting studies based on intracerebral injections of peptides, and advances our knowledge regarding the migration of compounds within the brain.

Animals↗
PubMed1986

Histology, immunohistochemistry, and ultrastructure of the verruga in Carrion's disease.

Twenty-six verruga peruana nodules were studied. The presence of Factor VIII-related antigen and Ulex europaeus lectin binding, and the ultrastructural finding of rudimentary cell junctions and pinocytotic vesicles establish the endothelial character of the proliferating cells in the verruga nodules. Whereas superficial lesions could show an angiomatoid pattern, deep-situated nodules tended to present a compact type of growth. Electron-microscopic studies have shown that Bartonella bacilliformis was found abundantly in the extracellular spaces in the florid lesions and that no organisms were present in the late, resolving subcutaneous nodules. Although no true intracellular "viable" microorganisms were noted, pseudopods of cytoplasm entrapping one or two bacteria and surrounding matrix substance were seen often. The characteristics of cytoplasmic inclusions previously described in verruga cells as "chlamydozoa" were detailed. The ultrastructure of the inclusions corresponded to endothelial phagocytic cells in which complex invaginations of the cell surface had produced a labyrinth of interconnected channels and vacuoles containing degraded bacteria, extracellular matrix components, or both. We conclude that in light microscopy the finding of Rocha-Lima's inclusions is the only definite morphologic evidence of the presence of bartonella in verruga lesions.

Antigens↗
PubMed1982

Human malignant diffuse mesothelioma: submicroscopic study on the epithelial component.

A submicroscopic analysis of eight cases of malignant diffuse mesothelioma was performed. Unlike normal and hyperplastic mesothelium, well differentiated neoplastic cells were found to have a prominent RER and a conspicuous Golgi system. By using a postfixation in osmium ferrocyanide, an amorphous substance was observed in the extracellular space. These features may be related to the ability of malignant diffuse mesothelioma to produce large amounts of hyaluronic acid. The significance of groups of membrane bound dense bodies found in seven of eight cases examined is also discussed.

Cell Membrane↗
PubMed1996

Extremely-low-frequency magnetic fields disrupt rhythmic slow activity in rat hippocampal slices.

Several studies have indicated that weak, extremely-low-frequency (ELF; 1-100 Hz) magnetic fields affect brain electrical activity and memory processes in man and laboratory animals. Our studies sought to determine whether ELF magnetic fields could couple directly with brain tissue and affect neuronal activity in vitro. We used rat hippocampal slices to study field effects on a specific brain activity known as rhythmic slow activity (RSA), or theta rhythm, which occurs in 7-15 s bursts in the hippocampus during memory functions. RSA, which, in vivo, is a cholinergic activity, is induced in hippocampal slices by perfusion of the tissue with carbachol, a stable analog of acetylcholine. We previously demonstrated that the free radical nitric oxide (NO), synthesized in carbachol-treated hippocampal slices, lengthened and destabilized the intervals between successive RSA episodes. Here, we investigate the possibility that sinusoidal ELF magnetic fields could trigger the NO-dependent perturbation of the rate of occurrence of the RSA episodes. Carbachol-treated slices were exposed for 10 min epochs to 1 or 60 Hz magnetic fields with field intensities of 5.6, 56, or 560 microT (rms), or they were sham exposed. All exposures took place in the presence of an ambient DC field of 45 microT, with an angle of -66 degrees from the horizontal plane. Sinusoidal 1 Hz fields at 56 and 560 microT, but not at 5.6 microT, triggered the irreversible destabilization of RSA intervals. Fields at 60 Hz resulted in similar, but not statistically significant, trends. Fields had no effects on RSA when NO synthesis was pharmacologically inhibited. However, field effects could take place when extracellular NO, diffusing from its cell of origin to the extracellular space,was chelated by hemoglobin. These results suggest that ELF magnetic fields exert a strong influence on NO systems in the brain; therefore, they could modulate the functional state of a variety of neuronal ensembles.

Animals↗
PubMed1993

Extracellular release of acetylcholine, noradrenaline and serotonin increases in the cerebral cortex during walking in conscious rats.

The effect of walking on the extracellular release of acetylcholine (ACh), noradrenaline (NA) and serotonin (5-HT) in the parietal lobe of the cerebral cortex was examined in conscious rats using the microdialysis technique. Walking at the speed of 2.3 m/min for 5 min produced significant increases in ACh, NA and 5-HT release in the cerebral cortical extracellular space. The increase in ACh release was the most prominent among the transmitters examined. It is suggested that the increased release of ACh in the cerebral cortex may contribute at least partly to the increases in the cerebral cortical blood flow during walking.

Acetylcholine↗
PubMed1999

Chloride-dependent transport of NH4+ into bee retinal glial cells.

Mammalian astrocytes convert glutamate to glutamine and bee retinal glial cells convert pyruvate to alanine. To maintain such amination reactions these glial cells may take up NH4+/NH3. We have studied the entry of NH4+/NH3 into bundles of glial cells isolated from bee retina by using the fluorescent dye BCECF to measure pH. Ammonium caused intracellular pH to decrease by a saturable process: the rate of change of pH was maximal for an ammonium concentration of about 5 mM. This acidifying response to ammonium was abolished by the loop diuretic bumetanide (100 microM) and by removal of extracellular Cl-. These results strongly suggest that ammonium enters the cell by contransport of NH4+ with Cl-. Removal of extracellular Na+ did not abolish the NH(4+)-induced acidification. The NH(4+)-induced pH change was unaffected when nearly all K+ conductance was blocked with 5 mM Ba2+ showing that NH4+ did not enter through Ba(2+)-sensitive ion channels. Application of 2 mM NH4+ led to a large increase in total intracellular proton concentration estimated to exceed 13.5 mEq/L. As the cell membrane appeared to be permeable to NH3, we suggest that when NH4+ entered the cells, NH3 left, so that protons were shuttled into the cell. This shuttle, which was strongly dependent on internal and external pH, was quantitatively modelled. In retinal slices, 2 mM NH4+ alkalinized the extracellular space: this alkalinization was reduced in the absence of bath Cl-. We conclude that NH4+ enters the glial cells in bee retina on a cotransporter with functional similarities to the NH4+(K+)-Cl- cotransporter described in kidney cells.

Animals↗
PubMed1985

Phosphorus nuclear magnetic resonance of fast- and slow-twitch muscle.

Phosphorus nuclear magnetic resonance (NMR) spectra were obtained at 109.3 MHz from isolated, arterially perfused cat biceps brachi (greater than 75% fast-twitch, glycolytic fibers) and soleus (greater than 92% slow-twitch, oxidative) muscles at 30 degrees C. The perfused muscles were stable with respect to O2 consumption, twitch characteristics, and ATP and phosphocreatine (PC) levels for up to 10 h. NMR spectra showed a higher PC/Pi ratio in the biceps (11) than in the soleus (1.7). Relatively higher Pi levels were observed in extracts of clamp-frozen muscles than in the intact muscles. This difference could be accounted for by artifactual hydrolysis of PC during muscle freezing. Based on the NMR and chemical data, the free cytosolic ADP level, calculated from the creatine kinase equilibrium, was 14 microM in the soleus and less than 1 microM in the biceps. Intracellular Pi concentration was 10 mM in the soleus and 3 mM in the biceps. Intracellular pH, estimated from the chemical shift of phosphate or 2-deoxyglucose 6-phosphate, was 7.0 in both muscles (perfusate pH 7.2). Both extracellular space and pH measurements were obtained from NMR spectra of muscles perfused with 10 mM sodium phenylphosphonate added to the perfusate. These results document larger differences in the phosphate metabolites in the two types of mammalian muscles than previously reported.

Adenosine Diphosphate↗
PubMed1983

Excitation-contraction coupling in frog ventricle. Possible Ca2+ transport mechanisms.

In frog ventricular muscle generation of tension was found to be under direct and continuous control of membrane potential. No phasic component of tension was found at any membrane potential. Developed tension depended only on the duration and amplitude of depolarization and was independent of previous contractile history. Developed tension, in part, depended on Ca2+ influx through a slowly inactivating component of Isi. Using long voltage clamp steps to achieve steady-state tension, no decline or reversal of developed tension was found at ECa. Increasing the [Ca]o shifted the tension-voltage relation to more negative potentials and increased the net outward current at potentials positive to -10 mV. The increase in tension seemed to be related to the increase in outward membrane current and K+ efflux, as estimated from post clamp K+ accumulations. Increasing [K]o, either by clamp-induced K+-accumulation or by increasing the [K] of the bathing solution, decreased the developed tension. These results suggest that in frog ventricular muscle Ca2+ for activation of tension is transported primarily from the extracellular space. There was no trigger-release of internal stores or recirculation of sequestered Ca2+. Activator Ca2+ was transported in part by a slowly inactivating Isi channel and a coupled transport mechanism. The exact mechanism by which Ca2+ transport and K+ efflux were related could not be identified.

Animals↗
PubMed1975

Some effects of intracerebral lead implantation in the rat.

Pellets of lead acetate were implanted into the forebrains of adult rats which were sacrificed at intervals between 4 days and 4 weeks thereafter. Parenchymal necrosis and a number of reactive changes including edema and macrophage invasion were observed. Lead deposits were found in the extracellular spaces and within macrophages but only to a slight extent within glial or meningeal cells. Vascular changes were quite remarkable and included proliferation and the appearance of fenestrated blood vessels as well as some with tubular bodies and striking increases in the number of pinocytotic vesicles.

Animals↗
PubMed1977

Experimental spongy degeneration in calves.

Experimental reproduction and ultrastructural findings of spongy degeneration of the central nervous system of hyperammonemic calves are described. Hyperammonemia was produced by intravenous infusion of ammonium acetate. Histologic findings were stereotyped in all calves and characterized by widespread vacuolation of white and grey matter of the brain spinal cord. Electron microscopy revealed widespread intramyelinic vacuoles, some expansion of extracellular spaces and swollen mitochondria. There were minimal changes in neurons, axons and glia, and little evidence of myelin breakdown. Hyperammonemia may be one of the pathogeneses involved in the CNS spongy degeneration in man and domestic animals effected with hepatocerebral diseases and some hereditary disorders.

Animals↗
PubMed1996

General properties of the resource consumption principle of neural function.

It has been proposed that volumes of neural tissue may represent important processing elements. This viewpoint suggests one way that populations of synaptic elements cooperate to implement important computational capacities. I extend this view by proposing a set of computational functions for the extracellular space shared by a local population of synapses. The critical hypothesis is the existence of a hypothetical 'fluid' resource present outside synapses that must be internalized in order for a synapse to function. I outline some of the consequences of assuming that such a resource is in limited supply on short time scales.

Animals↗
PubMed1986

Cerebral extracellular potassium concentration change and cerebral impedance change in short-term ischemia in gerbil.

Extracellular potassium and calcium ion concentration, field potential (Fp), local EEG and cortical impedance were measured continuously in the cortex and hippocampus of the pentobarbital anesthetized gerbils subjected to 5-minute ischemia produced by bilateral carotid occlusion. Extracellular potassium ([K+]e) and extracellular calcium ([Ca++]e) showed a triphasic change during ischemia followed by a biphasic change after recirculation. The EEG became flat within about 20 seconds. There was a sharp increase in the [K+]e and a sharp decrease in the [Ca++]e, which coincided with the sharp increase in the Fp around one and a half minutes. The impedance increased simultaneously with a large amplitude change of EEG. The [Ca++]e continued to decrease for another 1-2 minutes before returning to the normal values after recirculation whereas the [K+]e began to decrease immediately. The extracellular space (ECS) did not change until depolarization. The rise of the [K+]e and [Ca++]e in the pre-depolarization phase was not explained by the shrinkage of the ECS. The possible explanation for the change of the [Ca++]e in ischemia was discussed.

Action Potentials↗
PubMed1993

Serial long-term assessment of in vivo LHRH release from a discrete area of the ewe median eminence using multiple guide cannula assembly and removable push-pull cannulae.

Analysis of neuronal interactions at the median eminence (ME) that control anterior pituitary function requires sampling of in vivo release of specific hypophysiotropic components and of putative inputs that might regulate such a release. We developed a multiple guide cannula assembly (MGCA) to sample repetitively discrete areas of the ewe ME, using removable push-pull cannula (PPC) probes. The MGCA is attached to the skull over the ME using stereotaxic surgery. A specific guide cannula of the assembly (1 of 48 guides) located on the midline and directly on top of the central portion of the ME is selected based on roentgenograms obtained after infusion of radiopaque contrast material into the third ventricle. The MGCA and the large size of the ewe brain allows the simultaneous positioning of a PPC probe, an infusion cannula or another removable probe in additional discrete hypothalamic and extrahypothalamic areas. To determine the capabilities of this sampling technique, we assessed in vivo release of LHRH from the extracellular space at the posterior-lateral ME, under various reproductive conditions that have well-defined LH-secretory patterns. The pulsatile profile of both LHRH and LH was significantly lower in anestrus than during the follicular phase of cycling ewes. In vivo pulsatile release of LHRH was higher in the follicular than in the midluteal phase of ewes sampled repetitively from the same ME site during three consecutive estrous cycles. All ewes showed increased midluteal progesterone levels. In vivo LHRH release, as determined by PPC sampling of the extracellular fluid at the posterior-lateral ME, probably reflects a mix of hypophysiotropic and nonhypophysiotropic LHRH components. Histological analysis revealed a well-organized, pallisade-like array of astroglial processes along the track of chronically implanted cannulae. This glial scar is disrupted along the tracks of acutely reimplanted cannulae but without apparent difference in the yield of the method. Our method increases the efficiency and versatility of ME PPC sampling providing an additional tool to assess the role of the ME as the final neuroendocrine control site of anterior pituitary function.

Animals↗