RESUMO
Background: Patients who have had laryngectomy require a thorough preoperative assessment for potential stomal stenosis, and an action plan for possible inadvertent displacement of the voice prosthesis (VP) must be considered. We report the anesthetic management of a post-laryngectomy patient undergoing lung resection surgery. The patient had both a laryngectomy and a VP in situ. Case Description: A 66-year-old man with Parkinson's disease, who had previously undergone total laryngectomy for supraglottic laryngeal cancer, had a cuffed tracheostomy tube and a VP inserted into the tracheoesophageal fistula below it. He was scheduled for segmentectomy combined with lymph node dissection under combined epidural-general anesthesia due to lung cancer in the apical segment of the right lung. Following induction of general anesthesia, instead of using a double-lumen endotracheal tube, we inserted a long spiral single-lumen tube (SLT) (6 mm inner diameter, 8.7 mm outer diameter) through the tracheostoma under the guidance of a 4 mm bronchoscope because of concerns about airway injury due to the narrowed diameter of the stoma and potential dislodgement of the VP. The tube was carefully advanced and smoothly placed into the left main bronchus, and the surgery was completed using one-lung ventilation (OLV). Conclusions: For post-total laryngectomy patients, it is important to assess the size and condition of the tracheostoma and the usage of a VP, and choose an appropriate endotracheal tube. A long spiral SLT might be an option for OLV in patients after laryngectomy with a tracheoesophageal VP.
RESUMO
Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)-activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
Assuntos
Colesterol , Lisossomos , Alvo Mecanístico do Complexo 1 de Rapamicina , Receptores Acoplados a Proteínas G , Colesterol/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteoma/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Aliphatic diazirine analogues of cholesterol have been used previously to elaborate the cholesterol proteome and identify cholesterol binding sites on proteins. Cholesterol analogues containing the trifluoromethylphenyl diazirine (TPD) group have not been reported. Both classes of diazirines have been prepared for neurosteroid photolabeling studies and their combined use provided information that was not obtainable with either diazirine class alone. Hence, we prepared cholesterol TPD analogues and used them along with previously reported aliphatic diazirine analogues as photoaffinity labeling reagents to obtain additional information on the cholesterol binding sites of the pentameric Gloeobacter ligand-gated ion channel (GLIC). We first validated the TPD analogues as cholesterol substitutes and compared their actions with those of previously reported aliphatic diazirines in cell culture assays. All the probes bound to the same cholesterol binding site on GLIC but with differences in photolabeling efficiencies and residues identified. Photolabeling of mammalian (HEK) cell membranes demonstrated differences in the pattern of proteins labeled by the two classes of probes. Collectively, these date indicate that cholesterol photoaffinity labeling reagents containing an aliphatic diazirine or TPD group provide complementary information and will both be useful tools in future studies of cholesterol biology.
Assuntos
Colesterol/análogos & derivados , Diazometano/análogos & derivados , Canais Iônicos de Abertura Ativada por Ligante/química , Marcadores de Fotoafinidade/química , Alcinos/síntese química , Alcinos/química , Alcinos/metabolismo , Sítios de Ligação , Colesterol/síntese química , Colesterol/metabolismo , Cianobactérias/química , Diazometano/síntese química , Diazometano/metabolismo , Corantes Fluorescentes/química , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/metabolismo , Ligação ProteicaRESUMO
Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABAA receptor. The sites are located in the membrane-spanning domains of the receptor at the ß-α subunit interface (site I) and within the α (site II) and ß subunits (site III). Here, we have investigated the effects of mutations to these sites on potentiation of the rat α1ß2γ2L GABAA receptor by the endogenous neurosteroid allopregnanolone (3α5αP). The mutations were introduced alone or in combination to probe the additivity of effects. We show that the effects of amino acid substitutions in sites I and II are energetically additive, indicating independence of the actions of the two steroid binding sites. In site III, none of the mutations tested reduced potentiation by 3α5αP, nor did a mutation in site III modify the effects of mutations in sites I or II. We infer that the binding sites for 3α5αP act independently. The independence of steroid action at each site is supported by photolabeling data showing that mutations in either site I or site II selectively change steroid orientation in the mutated site without affecting labeling at the unmutated site. The findings are discussed in the context of linking energetic additivity to empirical changes in receptor function and ligand binding. SIGNIFICANCE STATEMENT: Prior work has identified three distinct binding sites for potentiating steroids in the heteromeric γ-aminobutyric acid type A receptor. This study shows that the sites act independently and additively in the presence of the steroid allopregnanolone and provide estimates of energetic contributions made by steroid binding to each site.
Assuntos
Substituição de Aminoácidos , Pregnanolona/farmacologia , Receptores de GABA-A/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Pregnanolona/química , Ratos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismoRESUMO
This study examines how site-specific binding to three identified neurosteroid-binding sites in the α1ß3 GABAA receptor (GABAAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3ß-epimer epi-allopregnanolone, binds to the canonical ß3(+)-α1(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the ß3 subunit, promoting receptor desensitization and the α1 subunit promoting effects that vary between neurosteroids. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind to all three sites, but do not potentiate GABAAR currents. KK148 is a desensitizing agent, whereas KK150 is devoid of allosteric activity. These compounds provide potential chemical scaffolds for neurosteroid antagonists. Collectively, these data show that differential occupancy and efficacy at three discrete neurosteroid-binding sites determine whether a neurosteroid has potentiating, inhibitory, or competitive antagonist activity on GABAARs.
Assuntos
Neuroesteroides , Receptores de GABA-A , Animais , Sítios de Ligação , Células Cultivadas , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Neuroesteroides/antagonistas & inibidores , Neuroesteroides/química , Neuroesteroides/metabolismo , Neuroesteroides/farmacologia , Oócitos/metabolismo , Pregnanolona/química , Pregnanolona/metabolismo , Pregnanolona/farmacologia , Ligação Proteica , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Xenopus laevisRESUMO
Muscimol is a psychoactive isoxazole derived from the mushroom Amanita muscaria and a potent orthosteric agonist of the GABAA receptor. The binding of [3H]muscimol has been used to evaluate the distribution of GABAA receptors in the brain, and studies of modulation of [3H]muscimol binding by allosteric GABAergic modulators such as barbiturates and steroid anesthetics have provided insight into the modes of action of these drugs on the GABAA receptor. It has, however, not been feasible to directly apply interaction parameters derived from functional studies to describe the binding of muscimol to the receptor. Here, we employed the Monod-Wyman-Changeux concerted transition model to analyze muscimol binding isotherms. We show that the binding isotherms from recombinant α1ß3 GABAA receptors can be qualitatively predicted using electrophysiological data pertaining to properties of receptor activation and desensitization in the presence of muscimol. The model predicts enhancement of [3H]muscimol binding in the presence of the steroids allopregnanolone and pregnenolone sulfate, although the steroids interact with distinct sites and either enhance (allopregnanolone) or reduce (pregnenolone sulfate) receptor function. We infer that the concerted transition model can be used to link radioligand binding and electrophysiological data. SIGNIFICANCE STATEMENT: The study employs a three-state resting-active-desensitized model to link radioligand binding and electrophysiological data. We show that the binding isotherms can be qualitatively predicted using parameters estimated in electrophysiological experiments and that the model accurately predicts the enhancement of [3H]muscimol binding in the presence of the potentiating steroid allopregnanolone and the inhibitory steroid pregnenolone sulfate.
Assuntos
Agonistas de Receptores de GABA-A/farmacologia , Muscimol/farmacologia , Receptores de GABA-A/metabolismo , Esteroides/farmacologia , Regulação Alostérica/efeitos dos fármacos , Sítios de Ligação , Células HEK293 , Humanos , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Muscimol/química , Pregnanolona/farmacologia , Pregnenolona/farmacologia , Receptores de GABA-A/química , Receptores de GABA-A/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Trítio/químicaRESUMO
Sevoflurane, a commonly used anesthetic in surgery, has drawn attention because of its preconditioning effects in hypoxic conditions. To investigate the preconditioning effects in the striatum, a common site for ischemic stroke, we collected whole-cell current-clamp recordings from striatal medium spiny neurons. In our in vitro brain slice experiments, deprivation of oxygen and glucose depolarized the striatal neurons to subthreshold potentials, and the pre-administration of sevoflurane (4%, 15 min) prolonged the time to depolarization. Furthermore, transient hypoxia induced the potentiation of excitatory postsynaptic potentials, which play a part in post-ischemic excitotoxicity. Glibenclamide, a KATP channel inhibitor, reversed the prolonged time to depolarization and the prevention of the pathological potentiation of excitatory responses, indicating that the short exposure to sevoflurane likely participates in neuroprotection against hypoxia via activation of KATP channels. A monocarboxylate transporter blocker, 4-CIN, also depolarized striatal neurons. Interestingly, the blockade of monocarboxylate transporters that supply lactate to neurons caused the pathological potentiation, even in the presence of enough oxygen and glucose. In this case, sevoflurane could not prevent the pathological potentiation, suggesting the involvement of monocarboxylate transporters in the sevoflurane-mediated effects. These results indicate that sevoflurane protects striatal neurons from hypoxic damage and alleviates the pathological potentiation. Under these conditions, sevoflurane may become an effective intervention for patients undergoing surgery.
Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Corpo Estriado/fisiologia , Hipóxia/fisiopatologia , Sevoflurano/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Glibureto/farmacologia , Masculino , Camundongos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Sevoflurano/antagonistas & inibidoresRESUMO
Voltage-dependent anion channel-1 (VDAC1) is a mitochondrial porin that is implicated in cellular metabolism and apoptosis, and modulated by numerous small molecules including lipids. VDAC1 binds sterols, including cholesterol and neurosteroids such as allopregnanolone. Biochemical and computational studies suggest that VDAC1 binds multiple cholesterol molecules, but photolabeling studies have identified only a single cholesterol and neurosteroid binding site at E73. To identify all the binding sites of neurosteroids in VDAC1, we apply photo-affinity labeling using two sterol-based photolabeling reagents with complementary photochemistry: 5α-6-AziP which contains an aliphatic diazirine, and KK200 which contains a trifluoromethyl-phenyldiazirine (TPD) group. 5α-6-AziP and KK200 photolabel multiple residues within an E73 pocket confirming the presence of this site and mapping sterol orientation within this pocket. In addition, KK200 photolabels four other sites consistent with the finding that VDAC1 co-purifies with five cholesterol molecules. Both allopregnanolone and cholesterol competitively prevent photolabeling at E73 and three other sites indicating that these are common sterol binding sites shared by both neurosteroids and cholesterol. Binding at the functionally important residue E73 suggests a possible role for sterols in regulating VDAC1 signaling and interaction with partner proteins.
Assuntos
Colesterol/metabolismo , Neuroesteroides/metabolismo , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Camundongos , Modelos Moleculares , Ligação Proteica , Canal de Ânion 1 Dependente de Voltagem/químicaRESUMO
Neurosteroids positively modulate GABA-A receptor (GABAAR) channel activity by binding to a transmembrane domain intersubunit site. Understanding the interactions in this site that determine neurosteroid binding and its effect is essential for the design of neurosteroid-based therapeutics. Using photo-affinity labeling and an ELIC-α1GABAAR chimera, we investigated the impact of mutations (Q242L, Q242W and W246L) within the intersubunit site on neurosteroid binding. These mutations, which abolish the thermal stabilizing effect of allopregnanolone on the chimera, reduce neither photolabeling within the intersubunit site nor competitive prevention of labeling by allopregnanolone. Instead, these mutations change the orientation of neurosteroid photolabeling. Molecular docking of allopregnanolone in WT and Q242W receptors confirms that the mutation favors re-orientation of allopregnanolone within the binding pocket. Collectively, the data indicate that mutations at Gln242 or Trp246 that eliminate neurosteroid effects do not eliminate neurosteroid binding within the intersubunit site, but significantly alter the preferred orientation of the neurosteroid within the site. The interactions formed by Gln242 and Trp246 within this pocket play a vital role in determining the orientation of the neurosteroid that may be necessary for its functional effect.
Assuntos
Neuroesteroides/química , Neuroesteroides/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Glutamina/química , Glutamina/genética , Glutamina/metabolismo , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Conformação Proteica , Domínios Proteicos , Receptores de GABA-A/genética , Homologia de Sequência , Triptofano/química , Triptofano/genética , Triptofano/metabolismoRESUMO
Cholesterol is an essential component of cell membranes, and is required for mammalian pentameric ligand-gated ion channel (pLGIC) function. Computational studies suggest direct interactions between cholesterol and pLGICs but experimental evidence identifying specific binding sites is limited. In this study, we mapped cholesterol binding to Gloeobacter ligand-gated ion channel (GLIC), a model pLGIC chosen for its high level of expression, existing crystal structure, and previous use as a prototypic pLGIC. Using two cholesterol analogue photolabeling reagents with the photoreactive moiety on opposite ends of the sterol, we identified two cholesterol binding sites: an intersubunit site between TM3 and TM1 of adjacent subunits and an intrasubunit site between TM1 and TM4. In both the inter- and intrasubunit sites, cholesterol is oriented such that the 3OH group points toward the center of the transmembrane domains rather than toward either the cytosolic or extracellular surfaces. We then compared this binding to that of the cholesterol metabolite, allopregnanolone, a neurosteroid that allosterically modulates pLGICs. The same binding pockets were identified for allopregnanolone and cholesterol, but the binding orientation of the two ligands was markedly different, with the 3OH group of allopregnanolone pointing to the intra- and extracellular termini of the transmembrane domains rather than to their centers. We also found that cholesterol increases, whereas allopregnanolone decreases the thermal stability of GLIC. These data indicate that cholesterol and neurosteroids bind to common hydrophobic pockets in the model pLGIC, GLIC, but that their effects depend on the orientation and specific molecular interactions unique to each sterol.
Assuntos
Colesterol/metabolismo , Canais Iônicos de Abertura Ativada por Ligante/fisiologia , Neurotransmissores/metabolismo , Sítios de Ligação/fisiologia , Membrana Celular/metabolismo , Colesterol/fisiologia , Cianobactérias/metabolismo , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Ligantes , Modelos Moleculares , Neurotransmissores/fisiologia , Marcadores de Fotoafinidade/metabolismo , Pregnanolona/metabolismo , Ligação Proteica/fisiologia , Domínios Proteicos/fisiologiaRESUMO
We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.
Assuntos
Artroplastia do Joelho/métodos , Dor Crônica/epidemiologia , Dor Pós-Operatória/epidemiologia , Toracotomia/métodos , Idoso , Idoso de 80 Anos ou mais , Analgésicos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Anestesia/efeitos adversos , Anestesia/métodos , Artroplastia do Joelho/efeitos adversos , Dor Crônica/etiologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pregabalina/administração & dosagem , Prevalência , Estudos Retrospectivos , Fatores de RiscoRESUMO
Volatile anesthetics have been reported to inhibit hyperpolarization-activated cyclic-nucleotide gated channels underlying the hyperpolarization-activated cation current (Ih) that contributes to generation of synchronized oscillatory neural rhythms. Meanwhile, the developmental change of Ih has been speculated to play a pivotal role during maturation. In this study, we examined the effect of the volatile anesthetic sevoflurane, which is widely used in pediatric surgery, on Ih and on functional Ih activation kinetics of cholinergic interneurons in developing striatum. Our analyses showed that the changes in Ih of cholinergic interneurons occurred in conjunction with maturation. Sevoflurane application (1-4%) caused significant inhibition of Ih in a dose-dependent manner, and apparently slowed Ih activation. In current-clamp recordings, sevoflurane significantly decreased spike firing during the rebound activation, which is essential for responses to the sensory inputs from the cortex and thalamus. The sevoflurane-induced inhibition of Ih in striatal cholinergic interneurons may lead to alterations of the acetylcholine-dopamine balance in the neural circuits during the early postnatal period.
Assuntos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/efeitos dos fármacos , Éteres Metílicos/farmacologia , Anestésicos/farmacologia , Animais , Córtex Cerebral/metabolismo , Estimulação Elétrica/métodos , Interneurônios/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Canais de Potássio/metabolismo , Sevoflurano , Tálamo/efeitos dos fármacosRESUMO
PURPOSE: We evaluated the hemodynamic and respiratory effects of dexmedetomidine in intubated, spontaneously breathing patients after endoscopic submucosal dissection (ESD) for cervical esophageal or pharyngeal cancer. METHODS: This retrospective study included 129 patients aged 66.5 ± 8.3 years, who underwent ESD under general anesthesia, and who were kept intubated overnight to prevent airway obstruction, receiving sedation with dexmedetomidine. Constant dexmedetomidine infusion at 0.51 ± 0.16 µg/kg/h was started intraoperatively (n = 109) or postoperatively (n = 20), following (n = 29) or not following (n = 100) loading doses, and continued until extubation. Hemodynamic and respiratory variables, and Richmond Agitation-Sedation Scale (RASS) score, were recorded. RESULTS: Postoperatively, 129 patients remained intubated while breathing spontaneously for 16.4 ± 3.3 h, and 124 patients could be sedated solely with dexmedetomidine, whereas 5 required rescue sedatives. During infusion, blood pressure decreased progressively until 12 h, whereas heart rate decreased only at 3 h. Hemodynamic alterations during dexmedetomidine infusion greatly depended not only on its hemodynamic effects but also on baseline hemodynamics before anesthesia. No serious adverse effect was noted. CONCLUSION: Dexmedetomidine in intubated, spontaneously breathing patients after ESD was safe and effective. Patient baseline hemodynamics could significantly affect hemodynamics during drug infusion. Without loading doses, plasma drug concentrations were expected to increase progressively. A progressive decrease in blood pressure and unchanged heart rate after an initial decrease suggested that hemodynamic effects of dexmedetomidine in our patients might differ from those reported in young volunteers, although further studies are required to elucidate these points.
Assuntos
Ressecção Endoscópica de Mucosa/métodos , Hipnóticos e Sedativos/administração & dosagem , Neoplasias Faríngeas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Extubação , Pressão Sanguínea/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Pessoa de Meia-Idade , Agitação Psicomotora/tratamento farmacológico , Respiração , Estudos RetrospectivosRESUMO
BACKGROUND: Duloxetine, an antidepressant, is used for treatment of pain, but the factors related to its effectiveness are not well known, and therefore we have performed a retrospective study. METHODS: Over a 22-month period from June 2012 patients with pain lasting for 3 months or more, with an NRS of 4 or higher, and given duloxetine within 3 months from their first diagnosis, were extracted from the medical records. These patients were compared and studied regarding their scores of the HADS (hos- pital anxiety and depression scale) at the time of first visit, duration of the disease, type of patient, and treat- ment effect after 1 month. RESULTS: The subjects were 61 patients, and they were categorized based on the presence of anxiety, the presence of dysphoria whether from organic or inor- ganic condition, and the duration of the disease, and no significant difference in the effectiveness of duloxetine was found. CONCLUSIONS: Duloxetine had an overall effectiveness of 50.8%, regardless of the presence of anxiety or depression, the duration of the disease and the type of diseases.
Assuntos
Antidepressivos/uso terapêutico , Dor Crônica , Cloridrato de Duloxetina/uso terapêutico , Adulto , Idoso , Ansiedade/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos RetrospectivosRESUMO
The volatile anesthetic sevoflurane, which is widely used in pediatric surgery, has proposed effects on GABAA receptor-mediated extrasynaptic tonic inhibition. In the developing striatum, medium-sized spiny projection neurons have tonic GABA currents, which function in the excitatory/inhibitory balance and maturation of striatal neural circuits. In this study, we examined the effects of sevoflurane on the tonic GABA currents of medium spiny neurons in developing striatal slices. Sevoflurane strongly increased GABAA receptor-mediated tonic conductance at postnatal days 3-35. The antagonist of the GABA transporter-1, 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride further increased tonic GABA conductance during the application of sevoflurane, thereby increasing the total magnitude of tonic currents. Both GABA (5 µM) and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride, the δ-subunit-containing GABAA receptor agonist, induced tonic GABA currents in medium spiny neurons but not in cholinergic neurons. However, sevoflurane additively potentiated the tonic GABA currents in both cells. Interestingly, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride-sensitive neurons made a large current response to sevoflurane, indicating the contribution of the δ-subunit on sevoflurane-enhanced tonic GABA currents. Our findings suggest that sevoflurane can affect the tone of tonic GABA inhibition in a developing striatal neural network.
Assuntos
Anestésicos Inalatórios/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Éteres Metílicos/farmacologia , Neostriado/efeitos dos fármacos , Neostriado/crescimento & desenvolvimento , Receptores de GABA-A/fisiologia , Animais , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Sevoflurano , Ácido gama-Aminobutírico/metabolismoAssuntos
Estenose da Valva Aórtica/cirurgia , Estenose Subaórtica Fixa/diagnóstico , Estenose da Valva Aórtica/diagnóstico por imagem , Cateterismo Cardíaco , Pré-Escolar , Estenose Subaórtica Fixa/diagnóstico por imagem , Ecocardiografia , Ecocardiografia Transesofagiana , Humanos , Período Intraoperatório , MasculinoRESUMO
The aim of this study was to evaluate the effects of nitrous oxide (a gaseous anesthetic) on the in vivo production of inflammatory cytokines and chemokines by the airway epithelium, when combined with sevoflurane or propofol. Subjects undergoing simple or segmental mastectomy were randomly assigned to the sevoflurane and nitrous oxide, sevoflurane and air, propofol and nitrous oxide, or propofol and air group (all n=13). Epithelial lining fluid (ELF) was obtained using the bronchoscopic microsampling method prior to and following the mastectomy to enable measurement of the pre- and post-operative levels of certain inflammatory cytokines and chemokines using a cytometric bead array system. Notably, the levels of interleukin (IL)-1ß, IL-8 and monocyte chemotactic protein-1 (MCP-1) in the ELF were significantly increased following the operations which involved the inhalation of sevoflurane and nitrous oxide, although the levels of these molecules were not significantly changed by the inhalation of sevoflurane and air. Furthermore, the IL-12p70 levels were significantly reduced in the ELF following the operations that involved the inhalation of sevoflurane and air, although the IL-12p70 levels were not significantly changed by the inhalation of nitrous oxide and sevoflurane. These observations suggest that the combination of sevoflurane and nitrous oxide induces an inflammatory response (increased production of IL-1ß, IL-8 and MCP-1) and suppresses the anti-inflammatory response (reduced production of IL-12p70) in the local milieu of the airway. Thus, the combination of these compounds should be carefully administered for anesthesia.
Assuntos
Anestesia , Quimiocinas/biossíntese , Éteres Metílicos/farmacologia , Óxido Nitroso/farmacologia , Propofol/farmacologia , Mucosa Respiratória/metabolismo , Adulto , Idoso , Anestésicos Inalatórios/administração & dosagem , Líquidos Corporais/efeitos dos fármacos , Líquidos Corporais/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Éteres Metílicos/administração & dosagem , Pessoa de Meia-Idade , Propofol/administração & dosagem , Mucosa Respiratória/efeitos dos fármacos , Sevoflurano , Adulto JovemRESUMO
PURPOSE: To assess the impact of stroke volume index (SVI) at the end of esophagectomy upon postoperative renal function. METHODS: We reviewed medical records of 128 patients undergoing esophagectomy. Intraoperative hemodynamics were monitored with the FloTrac sensor/Vigileo monitor system in addition to standard monitors. Patients were divided into two groups according to SVI at the end of surgery: the normal SVI group (n = 76), with SVI ≥ 35 ml/m2, and the low SVI group (n = 52), with SVI<35 ml/m2. We compared postoperative renal function, indicated by serum creatinine and estimated glomerular filtration rate, on post-operative days 0 through 3. We also compared numbers of patients who developed postoperative acute kidney injury (AKI). RESULTS: Although there were no intergroup differences in preoperative renal function or other intraoperative hemodynamic variables, including arterial pressure, central venous pressure, stroke volume variation, a volume of infusion, urine output, and the total intraoperative in-out balance, estimated glomerular filtration rate was significantly lower and serum creatinine was significantly higher in the low SVI group than in the normal SVI group on postoperative days 1 and 2 (P<0.05). In addition, more patients developed postoperative AKI in the low SVI group than in the normal SVI group (12 of 52 vs. 5 of 76, P = 0.015). CONCLUSIONS: Low SVI at the end of esophagectomy may represent a risk factor for AKI in the early postoperative period. Further studies are required to examine whether maintaining SVI above 35 ml/m2 reduces the incidence of AKI after esophagectomy.
Assuntos
Injúria Renal Aguda/diagnóstico , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Hipovolemia/diagnóstico , Monitorização Fisiológica/métodos , Complicações Pós-Operatórias , Volume Sistólico , Injúria Renal Aguda/etiologia , Idoso , Pressão Venosa Central , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hemodinâmica , Humanos , Hipovolemia/etiologia , Testes de Função Renal , Masculino , Prontuários Médicos , Monitorização Fisiológica/instrumentação , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: We examined the effects of dexamethasone, droperidol, naloxone, and a combination of these three agents on postoperative nausea and vomiting (PONV) in female patients. METHODS: In this randomized, controlled study, 120 female patients with ASA PS I or II undergoing laparoscopic gynecological surgery were randomly allocated into four groups. Patients received dexamethasone 8 mg (Dx group) or droperidol 1 mg (Dr group) before induction of general anesthesia. Anesthesia was induced and maintained with propofol and remifentanil. Postoperative analgesia was provided by intravenous patient-controlled analgesia using a disposable infusion pump filled with fentanyl 20 µg/kg alone (Dx group), fentanyl 20 µg/kg with droperidol 2 mg (Dr group), fentanyl 20 µg/kg with naloxone 0.1 mg (Nx group), or fentanyl 20 µg/kg with droperidol 2 mg and naloxone 0.1 mg (Cm group) in a total volume of 80 ml, with a constant infusion rate of 4 ml/h and a bolus dose 2 ml with a 30-min lockout time. RESULTS: The number of patients who developed PONV and required a rescue antiemetic was significantly less in the Cm group than in the Nx group (p < 0.001 for all). The incidence of PONV was 43, 43, 70, and 17 % in the Dx, Dr, Nx, and Cm groups, respectively. CONCLUSION: A combination of naloxone, droperidol, and dexamethasone was effective for preventing PONV in patients receiving fentanyl for postoperative analgesia after laparoscopic gynecological surgery, although further investigations are required to examine the effect of adding naloxone to other antiemetics.