[Central GABA-A receptor and anesthesia].
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Anesthetics, General↗
Biomedical subjects
I Uchida
Publications and source records attributed to I Uchida.
Transient brain activity used in magnetic resonance imaging to detect functional areas.
Functional areas were detected with short stimuli eliciting transient brain activity using the method of 'transient' regions of interest (ROIs) and functional magnetic resonance imaging (fMRI). This method was validated by comparing the results with sustainedly activated areas identified conventionally. Eighty-eight and 89% of the total areas of transient ROIs derived from 0.2 and 2 s stimulation, respectively, were identified at 5-7 s and 5-9 s, respectively, after stimulus onset. Eighty-eight and 76%, respectively, of these areas overlapped 'conventional' ROIs derived from 20 s stimulation. These results suggest that the delineation of transient ROIs, by targeting a period approximately 7 s after transient neural activity, can be useful for fMRI studies of cognitive functions.
Adult↗
Synthesis and selective coronary vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers.
A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development.
Animals↗
The differential antagonism by bicuculline and SR95531 of pentobarbitone-induced currents in cultured hippocampal neurons.
In voltage clamped cultured hippocampal neurons, application of gamma-aminobutyric acid (GABA) or pentobarbitone induced chloride current in a dose-dependent manner. The dose dependence of these agonists were well described by ED50 and Hill coefficients of 14.7 +/- 7 microM and 1.2 +/- 0.5, and 299 +/- 17.3 microM and 1.6 +/- 0.1, for GABA and pentobarbitone, respectively. The effects of two GABAA receptor antagonists, bicuculline and 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyridazinium bromide (SR95531) were evaluated by co-application of increasing concentrations of the antagonists with a fixed equipotent (approximately ED30) dose of GABA or pentobarbitone. Both bicuculline and SR95531 blocked the GABA induced current with ID50 and Hill coefficients of 0.74 +/- 0.07 microM and 0.96 +/- 0.07, and 0.44 +/- 0.02 microM and 1.22 +/- 0.06, respectively. Bicuculline similarly blocked the pentobarbitone induced current with a ID50 and Hill coefficient of 0.69 +/- 0.04 microM and 1.2 +/- 0.1. However, pentobarbitone induced current was poorly blocked by SR95531 retaining 86.5% of current amplitude at a concentration of SR95531, 200 times the IC50 for GABA induced current. Current induced by etomidate, another intravenous general anesthetic with GABAA receptor agonistic property, is likewise resistant to SR95531 blockade. Three-dimensional modeling of bicuculline and SR95531 with alignment of the molecules along the suggested GABA-receptor binding moiety indicates that these two antagonist molecules have distinct steric properties. We suggest that GABA and pentobarbitone act at nearby but non-identical sites on the hippocampal GABAA receptor to open the chloride ionophore, and that these sites can be distinguished by bicuculline and SR95531. This is the first demonstration that the prototypic GABAA site antagonists bicuculline and SR95531 have different effects on currents induced by GABA and pentobarbitone.
Anesthetics, General↗
Cloning, nucleotide sequence and expression of the gene encoding the cellulose-binding protein 1 (CBP1) of Fibrobacter succinogenes S85.
The nucleotide sequence of the gene encoding the Fibrobacter succinogenes S85 cellulose-binding protein 1 (CBP1) has been determined. The gene encodes a protein of 1054 amino acids with a molecular mass of 118614. The deduced amino acid sequence of CBP1 showed an extensive similarity to the cellulose-binding domain of an endoglucanase (EGCCD) from Clostridium cellulolyticum and contained the reiterated regions. The cloned gene was inserted into an expression vector, pRSETA, and was expressed in E. coli as a fused protein with the peptide consisting of six consecutive histidine residues. The fused protein was detected by immunoblotting using antiserum against CBP1, and exhibited the cellulose-binding activities.
Amino Acid Sequence↗
The agonistic action of pentobarbital on GABAA beta-subunit homomeric receptors.
Murine gamma-aminobutyric acid type A (GABAA) receptor beta 1, beta 2, and beta 3 subunits were expressed in Xenopus oocytes and studied using the two electrode voltage clamp technique. Although all three beta-subunits were unresponsive to GABA when expressed as homomers, the intravenous general anaesthetics pentobarbital, etomidate and propofol induced currents in beta 2 and beta 3 homomers. The pentobarbital-induced currents in beta 3 homomers showed a dose dependence with an ED50 of 89 +/- 8.9 microM and a Hill coefficient of 0.94 +/- 0.08. Zinc (50 microM) blocked (61.1 +/- 5.6% of control) and 200 microM lanthanum potentiated (139 +/- 8.6% of control) the pentobarbital-induced current. This current was also blocked by picrotoxin but was insensitive to the GABAA receptor antagonist bicuculline. These observations indicate that the full expression of the agonistic action of GABA requires the presence of an alpha-subunit, in contrast to the agonistic action of intravenous general anesthetics, where the presence of a beta2 or beta 3-subunit is sufficient. The difference in the agonistic action of intravenous anaesthetics among these highly homologous beta-subunits suggests that the beta-subunit homomeric receptors may be useful to further define the molecular sites of action of intravenous general anaesthetics and other functional domains on GABAA receptors.
Animals↗
Mechanisms of etomidate potentiation of GABAA receptor-gated currents in cultured postnatal hippocampal neurons.
The effect of etomidate, an imidazole general anesthetic, on GABAA receptor function was studied in cultured hippocampal neurons. At a clinically relevant concentration of 4.1 microM, etomidate shifts the GABA dose response to the left (ED50 shift from 10.2 to 5.2 microM), with no change in the maximum current evoked by saturating concentrations of GABA. At a higher concentration of 82 microM, etomidate directly induces current in the absence of GABA. Etomidate selectively increases the amplitude and prolongs the duration of miniature inhibitory postsynaptic currents without significant effects on miniature inhibitory postsynaptic currents. The combined effects of etomidate on miniature inhibitory postsynaptic current amplitude and duration enhance the total charge transfer by 280% during a spontaneous synaptic event. Analysis of single channels opened by GABA indicates that 8.2 microM etomidate increases the probability of channels being open 13-fold and increases the effective channel open time two-fold. Given the present understanding of central inhibitory synapses, the effect of etomidate on channel kinetics is most likely to be the predominant mechanism which influences the synaptic function. In addition, etomidate, through its modulation of both channel kinetics and open probability, is likely to have a large impact on extrasynaptic GABAA receptor function.
Anesthetics, General↗
[The pathogenesis of Bacillus anthracis].
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Animals↗
Excision-activated chloride channels in cultured postnatal rat hippocampal neurons.
Chloride permeable intermediate conductance single channel events activated on patch excision were found in outside-out patches from cultured postnatal hippocampal neurons. A majority of the channels had a conductance of 83 +/- 2.1 pS when recorded in a symmetrical TEACl solution. Two other populations of channels with conductance values of 62 +/- 2.1 pS and 145 +/- 1.9 pS were also observed. The reversal potentials for these intermediate conductance Cl- channels coincided with that of the GABA activated channels. The channels characteristically appeared 5-15 min after patch excision, suggesting that these channels may be blocked by some diffusible factors under physiological conditions. Based on the measurements of channel burst durations while the channel was partially blocked, and the channel open times after complete relief from the block, the mechanism of blockade does not appear to be a simple open channel blockade. The high prevalence and its potential regulation by cytosolic factors suggest an important physiological role for these Cl- channels coupling neuronal excitability with cellular metabolism.
Animals↗
Functional mapping of the human colour centre with echo-planar magnetic resonance imaging.
Clinical studies of cerebral achromatopsia have suggested a colour centre in the human fusiform gyrus. By using functional magnetic resonance imaging, we examined whether the fusiform gyrus shows activity correlated with the perception of colour. We tested three stimulus conditions in which the subject maintained fixation: (i) a circular array of six coloured circles; (ii) the same as (i) except that each circle is equiluminant grey with its colour counterpart; and (iii) the same as (i) plus a clockwise shift of circles to neighbouring positions every 1 s. After termination of the stimulus, the subject perceived an after-image of circles with complementary colours in (i), but not in (iii). In condition (i), we found a focal signal increase in the posterior part of the fusiform gyrus. In condition (ii), the activation in the same locus during the stimulation period was weaker than that in (i). In condition (iii), the signal intensity after termination of the stimulus was weaker than that in (i). The colour effect and after-effect on activation of the fusiform gyrus observed here suggest its critical role in human colour perception.
Brain Mapping↗
Etomidate potentiation of GABAA receptor gated current depends on the subunit composition.
The role of the gamma 2 subunit in etomidate potentiation of GABAA receptor-gated chloride current was studied by whole cell patch clamp experiments on H293 cells expressing GABAA receptors. The GABAA receptor subunits alpha 1 beta 1 with or without the gamma 2 subunit expressed well, with an overall peak current of 157 +/- 42 pA/pF. At a clinically relevant concentration, etomidate potentiates the peak current induced by GABA equally well in receptors with or without the gamma 2 subunit. In contrast, the time course of current decay was prolonged only in receptors with the gamma 2 subunit. This gamma 2 subunit-dependent prolongation of the current time course was not blocked by the benzodiazepine receptor antagonist flumazenil. These results show that etomidate, an imidazole general anesthetic, interacts with the GABAA receptor in a gamma 2 subunit-dependent manner.
Action Potentials↗
A specific oligonucleotide probe based on 5S rRNA sequences for identification of Vibrio anguillarum and Vibrio ordalii.
An oligonucleotide DNA probe based on 5S rRNA sequence data was constructed for the identification of the fish pathogens, Vibrio anguillarum and Vibrio ordalii. Specificity of the probe was tested in a colony blot hybridization assay. The respective probe was found to be specific for both V. anguillarum and V. ordalii. No cross hybridization was observed against other fish pathogens and the closely related Vibrionaceae genera. This specific probe may be useful for rapid identification of V. anguillarum and V. ordalii.
Base Sequence↗
Increase of central nitric oxide during pentylenetetrazol-induced seizures in rats.
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Animals↗
Molecular cloning of an Actinobacillus pleuropneumoniae outer membrane lipoprotein (OmlA) from serotype 5a.
The gene encoding an outer membrane lipoprotein (OmIA) was cloned from Actinobacillus pleuropneumoniae strain NG-8 (serotype 5a). The deduced amino acid sequence of OmIA from strain NG-8 showed 61% identity to the OmIA from serotype 1 strain, which confers protective immunity to pigs. Southern blot analysis showed the presence of a sequence highly homologous to the omIA gene of strain NG-8 in strains of serotype 5a, 5b and 10. A specific serum against OmIA of NG-8 also detected a homologous protein in the strains of these serotypes. These data shows the presence of antigenic variability among A. pleuropneumoniae OmIA proteins.
Actinobacillus Infections↗
Production of interleukin-6 at operative wound sites in surgical patients.
BACKGROUND: Interleukin-6 (IL-6) plays a central role in the acute phase of inflammation after surgical injury. The serum concentration of IL-6 increases during an operation. The mechanisms of this increase in the serum IL-6 level, however, has not yet been fully clarified. STUDY DESIGN: To determine the possibility of production of IL-6 at the operative wound site and its regulation by humoral factors in surgical patients, the IL-6 secretion of biopsied skin obtained from an operative wound both before and after the operation were quantitated by using organ culture techniques. RESULTS: When skin explants obtained from the uninjured skin were cultivated and the amounts of IL-6 secreted into the culture medium were measured, IL-6 secretion increased exponentially during culture, which indicated that the stress of the skin incision induced IL-6 production. The skin specimens obtained from the operative wounds postoperatively secreted a significantly larger amount of IL-6 than those obtained from uninjured skin either preoperatively or postoperatively, implying that skin at the site of the operative wound had been more sensitized to produce IL-6 because of the surgical injury. The IL-6 secretion by skin explants was significantly enhanced either by tumor necrosis factor or interleukin-1, while it was inhibited by corticosteroids. CONCLUSIONS: Interleukin-6 production at the site of the operative wound is partly responsible for the elevation of the serum IL-6 level during the operation. Organ cultures of the skin explants may provide a feasible system for research on the cytokine networks in surgical patients.
Adrenal Cortex Hormones↗
Microamperometric estimation of photosynthesis inhibition in a single algal protoplast.
The single-cell level inhibition of photosynthesis by some chemicals was investigated from the light-irradiation induced response of intracellular oxygen reduction current at an ultramicroelectrode inserted into a single algal protoplast. The addition of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), an electron-transport inhibitor, decreased a current peak appeared immediately after the light irradiation. The pI50 value (the negative decadic logarithm of the concentration needed for 50% inhibition) was determined from the change in response patterns and found to be 6.9 for DCMU. 2,4-Dichlorophenoxyacetic acid (2,4-D), an auxin herbicide, showed no effect on photosynthesis in the effective concentration range. 2,4-Dinitrophenol (DNP), a proton carrier, accelerated the oxygen production upon light irradiation.
2,4-Dichlorophenoxyacetic Acid↗
Expression and cloning of migration inhibitory factor-related protein (MRP)8 and MRP14 in arthritis-susceptible rats.
Rat migration inhibitory factor-related protein 8 (MRP8) and MRP14 were identified during screening of a subtracted cDNA library generated to identify differences in gene expression between LEW/N and F344/N rats. The predicted amino acid sequence of rat MRP8 and MRP14 is 60-80% identical with that from human and mouse. Expression of these genes correlated with chronic inflammation in LEW/N rats, but were absent in F344/N rats which do not develop arthritis in response to streptococcal cell wall peptidoglycan-polysaccharide complexes (SCW). These differences suggest a role for MRP8 and MRP14 in susceptibility to SCW-induced chronic disease.
Amino Acid Sequence↗
Microring-ring electrode for manipulation of a single cell.
Dielectrophoretic manipulation of a single myeloma cell was carried out using microring-ring electrodes (tip radius, 3-5 microns). When a.c. voltages were applied, the cell nearby the electrode tip was forced to move and trapped at the tip due to dielectrophoretic force induced by locally intense electric field.
Cell Movement↗