Protein kinase C co-expression and the effects of halothane on rat skeletal muscle sodium channels.
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1. Voltage-gated Na channels, which are potential targets for general anaesthetics, are substrates for PKC, which phosphorylates a conserved site in the channel inactivation gate. We investigated the idea that PKC modulates the effect of volatile anaesthetics on Na channels via phosphorylation of this inactivation gate site. 2. Na currents through rat skeletal muscle Na channel alpha-subunits expressed in Xenopus oocytes were measured by two-microelectrode voltage clamp in the presence of the volatile anaesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluroethane). PKC activity was modulated by co-expression of a constitutively active PKC alpha-isozyme. 3. Halothane (0.4 mM) had no effect on Na currents. With co-expression of PKC, however, halothane dose-dependently enhanced the rate of Na current decay and caused a small, but statistically significant reduction in Na current amplitude. 4. The enhancement of Na current decay was absent in a Na channel mutant in which the inactivation gate phosphorylation site was disabled. Effects of halothane on amplitude were independent of this mutation. 5. Co-expression of a PKC alpha-isozyme permits an effect of halothane to hasten current decay and reduce current amplitude, at least in part through interaction with the inactivation gate phosphorylation site. We speculate that the interaction between halothane and Na channels is direct, and facilitated by PKC activity and by phosphorylation of a site in the channel inactivation gate. (+info)
Ventilatory compensation for inspiratory resistive loads during anaesthesia with halothane or isoflurane.
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We have analysed the ventilatory response to sustained inspiratory resistive loads in 14 patients, while awake and during halothane (n = 7) or isoflurane (n = 7) anaesthesia. Patients breathed halothane or isoflurane in oxygen at 1.2 minimum alveolar concentration (MAC). Inspiratory resistances of 0, 12 and 37 cm H2O litre-1 s were applied. Tidal volume (VT) was maintained with the greater loads. At the greatest resistance, a significant reduction in minute ventilation occurred in both awake (-18.9%) and anaesthetized states, with both halothane (-10.4%) and isoflurane (-14.5%). Ventilatory frequency decreased significantly from mean 14.6 (SD 4.7) to 12.5 (4.3) bpm in the awake state and during anaesthesia, with increasing inspiratory resistance (29.5 (3.6) to 23.7 (7.2) bpm and 25.8 (3.3) to 23.4 (4.0) bpm, respectively, for halothane and isoflurane) because inspiratory time (TI) was significantly longer (P < 0.01). End-tidal PCO2 increased by 0.3 kPa, on average, from baseline to the highest level of resistance (P < 0.01). Inspiratory occlusion pressure at 100 ms increased significantly with increased loading in all situations (P < 0.001). We found a similar pattern of ventilatory adaptation to sustained inspiratory flow resistive loads both in awake and anaesthetized states. VT was maintained at increased loads because of an increase in inspiratory neuromuscular output and inspiratory duration. (+info)
Ubiquitin metabolism affects cellular response to volatile anesthetics in yeast.
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To investigate the mechanism of action of volatile anesthetics, we are studying mutants of the yeast Saccharomyces cerevisiae that have altered sensitivity to isoflurane, a widely used clinical anesthetic. Several lines of evidence from these studies implicate a role for ubiquitin metabolism in cellular response to volatile anesthetics: (i) mutations in the ZZZ1 gene render cells resistant to isoflurane, and the ZZZ1 gene is identical to BUL1 (binds ubiquitin ligase), which appears to be involved in the ubiquitination pathway; (ii) ZZZ4, which we previously found is involved in anesthetic response, is identical to the DOA1/UFD3 gene, which was identified based on altered degradation of ubiquitinated proteins; (iii) analysis of zzz1Delta zzz4Delta double mutants suggests that these genes encode products involved in the same pathway for anesthetic response since the double mutant is no more resistant to anesthetic than either of the single mutant parents; (iv) ubiquitin ligase (MDP1/RSP5) mutants are altered in their response to isoflurane; and (v) mutants with decreased proteasome activity are resistant to isoflurane. The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity. Like zzz4 strains, zzz1 mutants are resistant to all five volatile anesthetics tested, suggesting there are similarities in the mechanisms of action of a variety of volatile anesthetics in yeast and that ubiquitin metabolism affects response to all the agents examined. (+info)
Detecting alveolar epithelial injury following volatile anesthetics by (99m)Tc DTPA radioaerosol inhalation lung scan.
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BACKGROUND: Many volatile anesthetics have long been thought to affect alveolar epithelial permeability. OBJECTIVE: The purpose of this study was to examine the acute effects of volatile anesthetics on the permeability of the alveolocapillary barrier to (99m)Tc DTPA. METHODS: Twenty-seven patients (24 females, 3 males, age 29-73 years) undergoing operation were enrolled in this study and grouped according to the type of anesthesia received. Group 1 patients were administered 1% halothane. Group 2 patients were given 1.5% isoflurane. Intravenous anesthesia without volatile anesthetics were used for group 3 patients. Before and after anesthesia, (99m)Tc DTPA radioaerosol inhalation lung scans were performed to detect alveolar epithelial injury due to volatile anesthetics. The negative slope of the regression line was designated as the (99m)Tc DTPA pulmonary clearance rate and was expressed in terms of percentage decrease in radioactivity per minute. RESULTS: In group 1, the (99m)Tc DTPA clearance rates were 1.26 +/- 0.34 and 1.29 +/- 0.38 before and after anesthesia, respectively. The difference was not significant (p > 0.05). In group 2, the rates were 0.76 +/- 0.20 and 1.10 +/- 0. 37, before and after anesthesia, respectively. The difference was significant (p < 0.05). In group 3, the clearance rates were 1.07 +/- 0.38 and 1.21 +/- 0.48, before and after anesthesia, respectively. The difference was not significant. CONCLUSIONS: Following isoflurane administration, the more rapid pulmonary clearance of (99m)Tc DTPA indicates that isoflurane increases the permeability of the alveolo-capillary barrier. (+info)
Gap junctional coupling and patterns of connexin expression among neonatal rat lumbar spinal motor neurons.
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Interneuronal gap junctional coupling is a hallmark of neural development whose functional significance is poorly understood. We have characterized the extent of electrical coupling and dye coupling and patterns of gap junction protein expression in lumbar spinal motor neurons of neonatal rats. Intracellular recordings showed that neonatal motor neurons are transiently electrically coupled and that electrical coupling is reversibly abolished by halothane, a gap junction blocker. Iontophoretic injection of Neurobiotin, a low molecular weight compound that passes across most gap junctions, into single motor neurons resulted in clusters of many labeled motor neurons at postnatal day 0 (P0)-P2, and single labeled motor neurons after P7. The compact distribution of dye-labeled motor neurons suggested that, after birth, gap junctional coupling is spatially restricted. RT-PCR, in situ hybridization, and immunostaining showed that motor neurons express five connexins, Cx36, Cx37, Cx40, Cx43, and Cx45, a repertoire distinct from that expressed by other neurons or glia. Although all five connexins are widely expressed among motor neurons in embryonic and neonatal life, Cx36, Cx37, and Cx43 continue to be expressed in many adult motor neurons, and expression of Cx45, and in particular Cx40, decreases after birth. The disappearance of electrical and dye coupling despite the persistent expression of several gap junction proteins suggests that gap junctional communication among motor neurons may be modulated by mechanisms that affect gap junction assembly, permeability, or open state. (+info)
Changes in electroencephalogram and autonomic cardiovascular activity during induction of anesthesia with sevoflurane compared with halothane in children.
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BACKGROUND: This study was design to assess clinical agitation, electroencephalogram (EEG) and autonomic cardiovascular activity changes in children during induction of anesthesia with sevoflurane compared with halothane using noninvasive recording of EEG, heart rate, and finger blood pressure. METHODS: Children aged 2-12 yr premedicated with midazolam were randomly assigned to one of three induction techniques: 7% sevoflurane in 100% O2 (group SevoRAPID); 2%, 4%, 6%, and 7% sevoflurane in 100% O2 (group SevoINCR); or 1%, 2%, 3%, and 3.5% halothane in 50% N2O-50% O2 (group HaloN2O). An additional group of children who received 7% sevoflurane in 50% N2O-50% O2 (group SevoN2O) was enrolled after completion of the study. Induction was videotaped. EEG, heart rate, and finger blood pressure were continuously recorded during induction until 5 min after tracheal intubation and analyzed in frequency domain using spectral analysis. RESULTS: Agitation was more frequent when anesthesia was induced with 100% O2 compared to the mixture of oxygen and nitrous oxide. No seizures were recorded in any group. In the four groups, induction of anesthesia was associated with an increase in EEG total spectral power and a shift toward the low-frequency bands. Sharp slow waves were present on EEG tracings of the three sevoflurane groups, whereas slow waves and fast rhythms (spindles) were observed in the halothane group. Sevoflurane induced a greater withdrawal of parasympathetic activity than halothane and a transient relative increase in sympathetic vascular tone at loss of eyelash reflex. CONCLUSIONS: Agitation observed during sevoflurane induction was not associated with seizures. Sevoflurane induction induced a marked inhibition of parasympathetic control of heart rate. (+info)
Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate-evoked dopamine release in rat striatal slices: evidence for direct presynaptic effects.
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BACKGROUND: Experimental data suggest that volatile anesthetics induce significant changes in extracellular dopamine concentrations in the striatum, a restricted but functionally important brain area. In the present study, the authors used a superfused slice preparation to examine the effects of halothane and isoflurane on both spontaneous and N-methyl-D-aspartate (NMDA)-evoked dopamine release in the striatum, and whether these effects involved actions of these anesthetics mediated by gamma-aminobutyric acid receptors in this structure. METHODS: Radioactivity collected from 5-min fractions was compared in the absence (basal release) or presence (evoked release) of NMDA alone and combined with various pharmacologic or anesthetic agents in slices of the dorsolateral striatum and synaptosomes of the whole striatum preloaded with 3H-dopamine and superfused with artificial cerebrospinal fluid. RESULTS: In tetrodotoxin-treated striatal slices, halothane and isoflurane significantly increased dopamine basal release (EC50 = 0.33 mM and 0.41 mM for halothane and isoflurane, respectively). Both agents decreased the NMDA-evoked dopamine release in both the absence (IC50 = 0.15 mM and 0.14 mM for halothane and isoflurane, respectively) and presence (IC50 = 0.15 mM for both halothane and isoflurane) of tetrodotoxin in slices, and in synaptosomes (IC50 = 0.19 mM for both halothane and isoflurane). NMDA-induced dopamine release was significantly enhanced by bicuculline, a gamma-aminobutyric acid receptor antagonist. Halothane and isoflurane inhibitory effects on NMDA-evoked dopamine release were significantly reduced in the presence of bicuculline. CONCLUSION: These results indicate that halothane and isoflurane decrease the NMDA-evoked dopamine release by acting directly at dopamine terminals in striatal slices. They support the involvement of both depression of presynaptic NMDA receptor-mediated responses and enhancement of gamma-aminobutyric acid receptor-mediated responses in these effects. (+info)
Exposure to cigarette smoke impairs alveolar macrophage functions during halothane and isoflurane anesthesia in rats.
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BACKGROUND: Smoking alters numerous alveolar macrophage functions and is an important risk factor for postoperative pulmonary complications. The authors therefore tested the hypothesis that smoke exposure impairs antimicrobial and proinflammatory responses in alveolar macrophages during halothane and isoflurane anesthesia with mechanical ventilation. METHODS: Thirty control rats and 30 rats exposed to cigarette smoke were mechanically ventilated with 1.5 minimum alveolar concentration halothane and isoflurane. Ten smoke-exposed and control animals were assigned to one of three different anesthetic durations (0, 2, and 6 h). The fraction of aggregated cells and cell distribution were determined. Opsonized and unopsonized phagocytosis was measured. Microbicidal activity was determined as the ability to kill Listeria monocytogenes. The expression of interleukin (IL)-1alpha, IL-1beta, IL-6, macrophage inflammatory protein-2, interferon-gamma, and tumor necrosis factor-alpha was measured by semiquantitative reverse-transcription polymerase chain reaction. Pulmonary lavage concentrations of these cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: During both halothane and isoflurane anesthesia, the fraction of aggregated macrophages increased, whereas unopsonized and opsonized phagocytosis and microbicidal activity decreased significantly over time in both groups. Responses observed in smoke-exposed rats were almost twice as great as those observed in the control rats. Gene expression and production of all proinflammatory cytokines except IL-6 increased 2-20-fold during anesthesia. The increases in IL-1beta, interferon-gamma, and tumor necrosis factor-alpha in the control rats were 1.5-8 times greater than those in the smoke-exposed rats. CONCLUSION: Antimicrobial and proinflammatory responses of alveolar macrophages during anesthesia were markedly suppressed by smoke exposure. Our data suggest that smoke exposure reduces the efficacy of immune defenses during anesthesia. (+info)