Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.359
Filtrar
2.
Am J Vet Res ; 82(3): 181-188, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33629899

RESUMO

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of methadone after IV or IM administration to isoflurane-anesthetized chickens. ANIMALS: 6 healthy adult Hy-Line hens. PROCEDURES: In a randomized crossover-design study, methadone (6 mg/kg) was administered IV and IM to isoflurane-anesthetized chickens with a 1-week washout period between experiments. Blood samples were collected immediately before and at predetermined time points up to 480 minutes after methadone administration. Plasma concentrations were determined by liquid chromatography-mass spectrometry, and appropriate compartmental models were fit to the plasma concentration-versus-time data. Cardiorespiratory variables were compared between treatments and over time with mixed-effect repeated-measures analysis. RESULTS: A 3-compartment model best described the changes in plasma methadone concentration after IV or IM administration. Estimated typical values for volumes of distribution were 692 mL/kg for the central compartment and 2,439 and 2,293 mL/kg for the first and second peripheral compartments, respectively, with metabolic clearance of 23.3 mL/kg/min and first and second distributional clearances of 556.4 and 51.8 mL/kg/min, respectively. Typical bioavailability after IM administration was 79%. Elimination half-life was 177 minutes, and maximum plasma concentration after IM administration was 950 ng/mL. Heart rate was mildly decreased at most time points beginning 5 minutes after IV or IM drug administration. CONCLUSIONS AND CLINICAL RELEVANCE: Disposition of methadone in isoflurane-anesthetized chickens was characterized by a large volume of distribution and moderate clearance, with high bioavailability after IM administration. Additional studies are warranted to assess pharmacokinetics and pharmacodynamics of methadone in awake chickens.


Assuntos
Isoflurano , Animais , Galinhas , Estudos Cross-Over , Feminino , Meia-Vida , Frequência Cardíaca , Metadona
4.
Ecotoxicol Environ Saf ; 207: 111270, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949927

RESUMO

Risk assessment is an important tool in predicting the possible risk to health. It heightens awareness by estimating the probability of adverse health effects in humans who are exposed to chemicals in the course of their work. Therefore, the present work aims to determine the occupational exposure of operating room staff to the volatile anesthetic gases, isoflurane and sevoflurane, and estimates non-cancer risk using the United States Environmental Protection Agency method. Air samples from the breathing zone of staff members were collected using the Occupational Safety and Health Administration Method 103 and analyzed using gas chromatography-mass spectroscopy. The results indicate that the measured concentrations of isoflurane and sevoflurane are below the National Institute of Occupational Safety and Health standard (2 ppm) for technicians and nurses, but not for anesthesiologists and surgeons. Moreover, the estimated non-cancer risk due to isoflurane is above the acceptable value for anesthesiologists (but acceptable for other occupational categories). A sensitivity analysis indicates that exposure time has the most effect on calculated risk (53.4%). Occupational exposure to anesthetic gases may endanger the health of operating room personnel. Therefore, control measures, such as daily testing of anesthetic devices, ensuring the effectiveness of ventilation systems, advanced scavenging methods, and regular training of staff are highly recommended.


Assuntos
Poluentes Ocupacionais do Ar/análise , Anestésicos Inalatórios/análise , Isoflurano/análise , Exposição Ocupacional/estatística & dados numéricos , Sevoflurano/análise , Humanos , Exposição Ocupacional/análise , Salas Cirúrgicas , Medição de Risco , Estados Unidos
5.
Magn Reson Imaging ; 75: 134-140, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127411

RESUMO

OBJECTIVE: Alfaxalone has been used increasingly in biomedical research and veterinary medicine of large animals in recent years. However, its effects on the cerebral blood flow (CBF) physiology and intrinsic neuronal activity of anesthetized brains remain poorly understood. METHODS: Four healthy adult rhesus monkeys were anesthetized initially with alfaxalone (0.125 mg/kg/min) or ketamine (1.6 mg/kg/min) for 50 min, then administrated with 0.8% isoflurane for 60 min. Heart rates, breathing beats, and blood pressures were continuously monitored. CBF data were collected using pseudo-continuous arterial spin-labeling (pCASL) MRI technique and rsfMRI data were collected using single-shot EPI sequence for each anesthetic. RESULTS: Both the heart rates and mean arterial pressure (MAP) remained more stable during alfaxalone infusion than those during ketamine administration. Alfaxalone reduced CBF substantially compared to ketamine anesthesia (grey matter, 65 ± 22 vs. 179 ± 38 ml/100g/min, p<0.001; white matter, 14 ± 7 vs. 26 ± 6 ml/100g/min, p < 0.05); In addition, CBF increase was seen in all selected cortical and subcortical regions of alfaxalone-pretreated monkey brains during isoflurane exposure, very different from the findings in isoflurane-exposed monkeys pretreated with ketamine. Also, alfaxalone showed suppression effects on functional connectivity of the monkey brain similar to ketamine. CONCLUSION: Alfaxalone showed strong suppression effects on CBF of the monkey brain.The residual effect of alfaxalone on CBF of isoflurane-exposed brains was evident and monotonous in all the examined brain regions when used as induction agent for inhalational anesthesia. In particular, alfaxalone showed similar suppression effect on intrinsic neuronal activity of the brain in comparison with ketamine. These findings suggest alfaxalone can be a good alternative to veterinary anesthesia in neuroimaging examination of large animal models. However, its effects on CBF and functional connectivity should be considered.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Ketamina/farmacologia , Pregnanodionas/farmacologia , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/farmacologia , Animais , Encéfalo/irrigação sanguínea , Frequência Cardíaca/efeitos dos fármacos , Isoflurano/administração & dosagem , Isoflurano/farmacologia , Macaca mulatta , Masculino , Pregnanodionas/administração & dosagem
6.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Isoflurano/antagonistas & inibidores , Isoflurano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Propofol/farmacologia , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Feto , Interleucina-6/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Sinaptofisina/metabolismo
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(5): 670-675, 2020 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-32897214

RESUMO

OBJECTIVE: To study the protective effect of isoflurane preconditioning on hepatic ischemia-reperfusion (I/R) injury mediated by the noncanonical pyroptosis pathway. METHODS: Thirty C57BL/6 mice were randomly divided into sham-operated group, isoflurane group and I/R group, and in the latter two groups, hepatic I/R injury was induced by clamping the portal vein for 30 min. In isoflurane group, the mice were pretreated with 1.4% isoflurane 30 min before the surgery. The protective effect of isoflurane preconditioning against hepatic I/R injury was evaluated by assessing the pathological score of HE staining of the liver tissue and serum ALT and AST levels. Serum IL-1ß and IL-18 levels and the protein expression of GSDMS were detected by ELISA and Western blotting to evaluate the inhibitory effect of isoflurane preconditioning on pyroptosis. Western blotting and immunofluroescence were used to detect the protein expression of caspase-11 in the liver tissues to evaluate the inhibitory effect of isoflurane preconditioning on noncanonical pyroptosis pathway. RESULTS: The Suzuki's score of the liver tissue was significantly higher in I/R group than in the sham group (P < 0.05), while the score in the isoflurane group was significantly lower than that in the I/R group (P < 0.05). Serum ALT and AST levels significantly increased in the sham group (P < 0.05), and were significantly lower in isoflurane group than in I/R group (P < 0.05). The serum levels of IL-1ß and IL-18 were significantly higher in I/R group than in sham group (P < 0.05), and were significantly lower in isoflurane group than in I/R group (P < 0.05). The expression of GSDMD in the I/R group was significantly higher than that in sham group, and was significantly lower in isoflurane group than in I/R group (P < 0.05). The hepatic expression of caspase-11 was significantly higher in I/R group than in sham group (P < 0.05), and was significantly lower in isoflurane group than in I/R group (P < 0.05). CONCLUSIONS: Isoflurane preconditioning has protective effect against hepatic I/R injury, which is related to the inhibition of the noncanonical pyroptosis pathway.


Assuntos
Precondicionamento Isquêmico , Traumatismo por Reperfusão , Animais , Caspases Iniciadoras , Isoflurano , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Piroptose
8.
Anesthesiology ; 133(4): 852-866, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930727

RESUMO

BACKGROUND: Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. METHODS: Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). RESULTS: Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). CONCLUSIONS: Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.


Assuntos
Anestésicos Inalatórios/toxicidade , Isoflurano/toxicidade , Receptores Androgênicos/fisiologia , Membro 2 da Família 12 de Carreador de Soluto/fisiologia , Fatores Etários , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
9.
Anesthesiology ; 133(4): 812-823, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773681

RESUMO

BACKGROUND: Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein-protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function. METHODS: One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice. RESULTS: Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes: (1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer]): control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P < 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P < 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index]): naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration]): Learning, control (69 ± 12) versus isoflurane (52 ± 13), P < 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P < 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P < 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline]): control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor. CONCLUSIONS: Early disruption of PDZ2 domain-mediated protein-protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.


Assuntos
Anestésicos Inalatórios/toxicidade , Cognição/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/antagonistas & inibidores , Isoflurano/toxicidade , Animais , Animais Recém-Nascidos , Cognição/fisiologia , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Proteína 4 Homóloga a Disks-Large/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Peptídeos/farmacologia , Densidade Pós-Sináptica/efeitos dos fármacos , Densidade Pós-Sináptica/patologia , Densidade Pós-Sináptica/fisiologia
10.
Anesthesiology ; 133(4): 839-851, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32773682

RESUMO

BACKGROUND: General anesthetics influence mitochondrial homeostasis, placing individuals with mitochondrial disorders and possibly carriers of recessive mitochondrial mutations at increased risk of perioperative complications. In Drosophila, mutations in the ND23 subunit of complex I of the mitochondrial electron transport chain-analogous to mammalian NDUFS8-replicate key characteristics of Leigh syndrome, an inherited mitochondrial disorder. The authors used the ND23 mutant for testing the hypothesis that anesthetics have toxic potential in carriers of mitochondrial mutations. METHODS: The authors exposed wild-type flies and ND23 mutant flies to behaviorally equivalent doses of isoflurane or sevoflurane in 5%, 21%, or 75% oxygen. The authors used percent mortality (mean ± SD, n ≥ 3) at 24 h after exposure as a readout of toxicity and changes in gene expression to investigate toxicity mechanisms. RESULTS: Exposure of 10- to 13-day-old male ND23 flies to isoflurane in 5%, 21%, or 75% oxygen resulted in 16.0 ± 14.9% (n = 10), 48.2 ± 16.1% (n = 9), and 99.2 ± 2.0% (n = 10) mortality, respectively. Comparable mortality was observed in females. In contrast, under the same conditions, mortality was less than 5% for all male and female groups exposed to sevoflurane, except 10- to 13-day-old male ND23 flies with 9.6 ± 8.9% (n = 16) mortality. The mortality of 10- to 13-day-old ND23 flies exposed to isoflurane was rescued by neuron- or glia-specific expression of wild-type ND23. Isoflurane and sevoflurane differentially affected expression of antioxidant genes in 10- to 13-day-old ND23 flies. ND23 flies had elevated mortality from paraquat-induced oxidative stress compared with wild-type flies. The mortality of heterozygous ND23 flies exposed to isoflurane in 75% oxygen increased with age, resulting in 54.0 ± 19.6% (n = 4) mortality at 33 to 39 days old, and the percent mortality varied in different genetic backgrounds. CONCLUSIONS: Mutations in the mitochondrial complex I subunit ND23 increase susceptibility to isoflurane-induced toxicity and to oxidative stress in Drosophila. Asymptomatic flies that carry ND23 mutations are sensitized to hyperoxic isoflurane toxicity by age and genetic background.


Assuntos
Anestésicos Inalatórios/toxicidade , Complexo I de Transporte de Elétrons/genética , Isoflurano/toxicidade , Mitocôndrias/genética , Mutação/genética , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Animais Geneticamente Modificados , Drosophila , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mutação/efeitos dos fármacos , Sevoflurano/toxicidade
11.
Anesthesiology ; 133(3): 534-547, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784343

RESUMO

BACKGROUND: According to the "three-compartment" model of ventilation-perfusion ((Equation is included in full-text article.)) inequality, increased (Equation is included in full-text article.)scatter in the lung under general anesthesia is reflected in increased alveolar deadspace fraction (VDA/VA) customarily measured using end-tidal to arterial (A-a) partial pressure gradients for carbon dioxide. A-a gradients for anesthetic agents such as isoflurane are also significant but have been shown to be inconsistent with those for carbon dioxide under the three-compartment theory. The authors hypothesized that three-compartment VDA/VA calculated using partial pressures of four inhalational agents (VDA/VAG) is different from that calculated using carbon dioxide (VDA/VACO2) measurements, but similar to predictions from multicompartment models of physiologically realistic "log-normal" (Equation is included in full-text article.)distributions. METHODS: In an observational study, inspired, end-tidal, arterial, and mixed venous partial pressures of halothane, isoflurane, sevoflurane, or desflurane were measured simultaneously with carbon dioxide in 52 cardiac surgery patients at two centers. VDA/VA was calculated from three-compartment model theory and compared for all gases. Ideal alveolar (PAG) and end-capillary partial pressure (Pc'G) of each agent, theoretically identical, were also calculated from end-tidal and arterial partial pressures adjusted for deadspace and venous admixture. RESULTS: Calculated VDA/VAG was larger (mean ± SD) for halothane (0.47 ± 0.08), isoflurane (0.55 ± 0.09), sevoflurane (0.61 ± 0.10), and desflurane (0.65 ± 0.07) than VDA/VACO2 (0.23 ± 0.07 overall), increasing with lower blood solubility (slope [Cis], -0.096 [-0.133 to -0.059], P < 0.001). There was a significant difference between calculated ideal PAG and Pc'G median [interquartile range], PAG 5.1 [3.7, 8.9] versus Pc'G 4.0[2.5, 6.2], P = 0.011, for all agents combined. The slope of the relationship to solubility was predicted by the log-normal lung model, but with a lower magnitude relative to calculated VDA/VAG. CONCLUSIONS: Alveolar deadspace for anesthetic agents is much larger than for carbon dioxide and related to blood solubility. Unlike the three-compartment model, multicompartment (Equation is included in full-text article.)scatter models explain this from physiologically realistic gas uptake distributions, but suggest a residual factor other than solubility, potentially diffusion limitation, contributes to deadspace.


Assuntos
Anestésicos Inalatórios/farmacocinética , Desflurano/farmacocinética , Halotano/farmacocinética , Isoflurano/farmacocinética , Alvéolos Pulmonares/metabolismo , Sevoflurano/farmacocinética , Idoso , Artérias/fisiologia , Dióxido de Carbono/metabolismo , Feminino , Humanos , Pulmão/metabolismo , Masculino , Pressão Parcial , Estudos Prospectivos , Estudos Retrospectivos
12.
Anesthesiology ; 133(5): 1046-1059, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32826405

RESUMO

BACKGROUND: The degree to which different volatile anesthetics depress carotid body hypoxic response relates to their ability to activate TASK potassium channels. Most commonly, volatile anesthetic pairs act additively at their molecular targets. We examined whether this applied to carotid body TASK channels. METHODS: We studied halothane and isoflurane effects on hypoxia-evoked rise in intracellular calcium (Ca2+i, using the indicator Indo-1) in isolated neonatal rat glomus cells, and TASK single-channel activity (patch clamping) in native glomus cells and HEK293 cell line cells transiently expressing TASK-1. RESULTS: Halothane (5%) depressed glomus cell Ca2+i hypoxic response (mean ± SD, 94 ± 4% depression; P < 0.001 vs. control). Isoflurane (5%) had a less pronounced effect (53 ± 10% depression; P < 0.001 vs. halothane). A mix of 3% isoflurane/1.5% halothane depressed cell Ca2+i response (51 ± 17% depression) to a lesser degree than 1.5% halothane alone (79 ± 15%; P = 0.001), but similar to 3% isoflurane alone (44 ± 22%; P = 0.224), indicating subadditivity. Halothane and isoflurane increased glomus cell TASK-1/TASK-3 activity, but mixes had a lesser effect than that seen with halothane alone: 4% halothane/4% isoflurane yielded channel open probabilities 127 ± 55% above control, versus 226 ± 12% for 4% halothane alone (P = 0.009). Finally, in HEK293 cell line cells, progressively adding isoflurane (1.5 to 5%) to halothane (2.5%) reduced TASK-1 channel activity from 120 ± 38% above control, to 88 ± 48% (P = 0.034). CONCLUSIONS: In all three experimental models, the effects of isoflurane and halothane combinations were quantitatively consistent with the modeling of weak and strong agonists competing at a common receptor on the TASK channel.


Assuntos
Anestésicos Inalatórios/metabolismo , Corpo Carotídeo/metabolismo , Halotano/metabolismo , Isoflurano/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Corpo Carotídeo/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Combinação de Medicamentos , Interações Medicamentosas/fisiologia , Células HEK293 , Halotano/farmacologia , Humanos , Isoflurano/farmacologia
14.
Life Sci ; 258: 118154, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735882

RESUMO

AIMS: Epithelial-to-mesenchymal transition (EMT) facilitates cell migration and invasion, and contributes to metastasis in bladder cancer. Within the perioperative period, anesthetic such as isoflurane have been found to affect cancer prognosis. In the study, we reported the tumor-promoting effect of isoflurane in bladder cancer. MATERIALS AND METHODS: Human bladder cancer cell lines T24 and BIU-87 were exposed to isoflurane at different concentrations. The immunofluorescent staining of Ki67, Annexin V-FITC/PI staining, Transwell invasion assays and wound-healing assays were performed to assess cell proliferation, apoptosis, invasion and migration. Expressions of EMT markers (E-cadherin, N-cadherin and Vimentin) and metastatic markers (Snail-1, Slug-1 and MMP-2/9) were determined by immunoblotting. Orthotopic tumor models and mice given tail vein injection of T24 cells were developed with or without 4-h exposure to 2% isoflurane. KEY FINDINGS: We found isoflurane promoted bladder cancer cell proliferation, invasion and migration but reduce apoptosis in a concentration-dependent manner. In addition, isoflurane was shown to increase HIF-1α and its nuclear accumulation in bladder cancer cells. HIF-1α knockdown inhibited bladder cancer cell proliferation and delayed EMT, which was reversed in the presence of 4-h exposure to 2% isoflurane. Likewise, we found isoflurane modulated ß-catenin/Notch1 pathways via HIF-1α. In vivo studies showed that isoflurane exposure accelerated formation of orthotopic bladder tumor and promoted hepatic metastases from carcinoma of the bladder. SIGNIFICANCE: Taken together, our study demonstrates that a frequently used anesthetic can exert a protumorigenic effect on bladder cancer. Isoflurane may serve as an important contributory factor to high recurrence following surgery.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Isoflurano/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/induzido quimicamente , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Receptor Notch1/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , beta Catenina/metabolismo
15.
Zhonghua Yi Xue Za Zhi ; 100(29): 2278-2282, 2020 Aug 04.
Artigo em Chinês | MEDLINE | ID: mdl-32746598

RESUMO

Objective: To analyze the effects of desflurane and sevoflurane anesthesia on postoperative recovery after long lasting tumor surgery. Methods: One hundred and sixty patients undergoing endoscopic radical esophagectomy and gastrectomy (80 cases of each surgical type) from November 2019 to March 2020 at Henan Cancer Hospital, were randomized into 4 groups(n=40): group CS (esophageal cancer+sevoflurane anesthesia), group DS (esophageal cancer+desflurane anesthesia),group CW (stomach cancer+sevoflurane anesthesia) and group DW (gastric cancer+desflurane anesthesia). General anesthesia was induced by intravenous agents in all four groups, which were maintained by inhaled anesthetic during the operation. The mean arterial pressure (MAP), heart rate (HR), and surplus pulse O(2) (SpO(2)) immediately before induction (T(1)), the moment of operation begin (T(2)), operation end (T(3)) and extubation (T(4)) were recorded. Also, the duration required for inhalation anesthetic alveolar concentration reaching 0.5 minimum alveolar concentration (MAC) during induction, the alveolar anesthetic concentration at the beginning of the operation, the duration required for XMAC (patients specific alveolar concentration) declining to 0.5 MAC on recovery period, and the duration of alveolar concentration of 0.5 MAC declining to 0.2 MAC were determined. Additionally, the durations of spontaneous breathing recovery, eyes opening, extubation and recovery of consciousness were recorded. Finally, restlessness score (RS) during recovery period was used to evaluate postoperative agitation. Results: Compared with group CS and group CW, no significant differences in MAP, HR, SpO(2) in group DS and group DW at T(1) to T(4) were found (all P>0.05). The durations required for inhalation anesthetic alveolar concentration reaching 0.5 MAC were (5.6±1.3), (5.8±2.1), (3.5±1.5) and (3.8±1.0) min in group CS, group CW, group DS and group DW, where the durations in group DS and group DW were significantly shorter than those in group CS and group CW (F=32.538, P<0.05). The durations of alveolar concentration of 0.5 MAC declining to 0.2 MAC were (6.4±2.2), (7.0±1.5), (4.2±2.2) and (4.1±1.5) min in group CS, group CW, group DS and group DW, and the durations in group DS and group DW were significantly shortened as compared with group CS and group CW (F=42.113, P<0.05). Compared with group CS and group CW, group DS and group DW required significantly shorter time for spontaneous breathing recovery, eye opening,extubation, and directional force recovery after operation (all P<0.05). Conclusions: Both desflurane and sevoflurane anesthesia can achieve satisfactory anesthesia depth during long lasting tumor surgery. Desflurane can shorten the recovery time and early extubation, and improve the quality of recovery.


Assuntos
Período de Recuperação da Anestesia , Anestésicos Inalatórios , Isoflurano , Éteres Metílicos , Neoplasias , Desflurano , Humanos , Sevoflurano
16.
Br J Anaesth ; 125(3): 308-320, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660718

RESUMO

BACKGROUND: Recent studies point to a fundamental distinction between population-based and individual-based anaesthetic pharmacology. At the population level, anaesthetic potency is defined as the relationship between drug concentration and the likelihood of response to a stimulus. At the individual level, even when the anaesthetic concentration is held constant, fluctuations between the responsive and unresponsive states are observed. Notably, these spontaneous fluctuations exhibit resistance to state transitions Rst. Therefore, the response probability in each individual depends not just upon the drug concentration, but also upon responses to previous stimuli. Here, we hypothesise that Rst is distinct from drug potency and is differentially modulated by different anaesthetics. METHODS: Adult (14-24 weeks old) C57BL/6J male mice (n=60) were subjected to repeated righting reflex (RR) assays at equipotent steady-state concentrations of isoflurane (0.6 vol%), sevoflurane (1.0 vol%), and halothane (0.4 vol%). RESULTS: Fluctuations in RR were observed for all tested anaesthetics. Analysis of these fluctuations revealed that Rst was differentially modulated by different anaesthetics (F[2, 56.01]=49.59; P<0.0001). Fluctuations in RR were modelled using a stochastic dynamical system. This analysis confirmed that the amount of noise that drives behavioural state transitions depends on the anaesthetic agent (F[2, 42.86]=16.72; P<0.0001). CONCLUSIONS: Whilst equipotent doses of distinct anaesthetics produce comparable population response probabilities, they engage dramatically different dynamics in each individual animal. This manifests as a differential aggregate propensity to exhibit state transitions. Thus, resistance to state transitions is a fundamentally distinct, novel measure of individualised anaesthetic pharmacology.


Assuntos
Anestésicos Inalatórios/farmacologia , Halotano/farmacologia , Isoflurano/farmacologia , Reflexo de Endireitamento/efeitos dos fármacos , Sevoflurano/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais
17.
Adv Clin Exp Med ; 29(6): 695-700, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32598581

RESUMO

BACKGROUND: Isoflurane preconditioning could reduce different kinds of brain injury via sphingosine kinase (SPK). Both sphingosine kinase 1 and sphingosine kinase 2 play important roles in brain protection. However, the effects of isoflurane preconditioning on SPK expression in hypertension have not been investigated before. OBJECTIVES: To verify whether the neuroprotective effects of the anesthetic isoflurane after an ischemic injury are altered in hypertension and to identify its possible mechanisms involving SPK. MATERIAL AND METHODS: Wistar rats (control) and spontaneous hypertension rats (SHR) were exposed to isoflurane preconditioning before transient middle cerebral artery occlusion. The infarct volumes of cortical and subcortical brain areas were measured. The expression levels of SPK1 and SPK2 were measured before and after isoflurane preconditioning. RESULTS: In the SHR group, isoflurane preconditioning significantly reduced only the infarct volumes of the subcortical brain (p < 0.05), not of the cortical brain. After 3 h of isoflurane exposure and preconditioning, SPK2 levels in the SHR group increased in the cortical brain (p < 0.05), but not in the subcortical brain area, Unlike in the control group, isoflurane exposure and preconditioning could significantly increase SPK2 levels in both cortical and subcortical brain area. CONCLUSIONS: The brain protection effects induced by isoflurane preconditioning after an ischemic injury are mainly mediated by the SPK2 isoform and are somewhat impaired in hypertension. Attention should be paid to ischemic injury patients with hypertension.


Assuntos
Anestésicos Inalatórios , Isquemia Encefálica , Hipertensão , Precondicionamento Isquêmico , Isoflurano , Fosfotransferases (Aceptor do Grupo Álcool) , Anestésicos Inalatórios/farmacologia , Animais , Isquemia Encefálica/prevenção & controle , Humanos , Isoflurano/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ratos , Ratos Wistar , Esfingosina
18.
Intensive Care Med ; 46(8): 1563-1566, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32588067

RESUMO

Hospitals worldwide are experiencing a shortage in essential intravenous sedative medications. This is attributable to high number and high sedative needs of COVID-19 critical care patients with disruption of drug supply chains. Inhaled volatile anesthetic agents are an abundant resource and readily implementable solution for providing ICU sedation. Inhaled volatile agents may also provide important pulmonary benefits for COVID-19 patients with ARDS that could improve gas exchange and reduce time spent on a ventilator. We review the use of volatile agents, and provide a technical overview and algorithm for administering inhaled volatile-based sedation in ICUs.


Assuntos
Anestésicos Inalatórios , Betacoronavirus , Infecções por Coronavirus/complicações , Hipnóticos e Sedativos/administração & dosagem , Pneumonia Viral/terapia , /terapia , Algoritmos , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/provisão & distribução , Humanos , Isoflurano , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/etiologia , Sevoflurano/efeitos adversos
19.
PLoS One ; 15(6): e0235046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579566

RESUMO

Post-ictal emergence of slow wave EEG (electroencephalogram) activity and burst-suppression has been associated with the therapeutic effects of the electroconvulsive therapy (ECT), indicating that mere "cerebral silence" may elicit antidepressant actions. Indeed, brief exposures to burst-suppressing anesthesia has been reported to elicit antidepressant effects in a subset of patients, and produce behavioral and molecular alterations, such as increased expression of brain-derived neurotrophic factor (BDNF), connected with antidepressant responses in rodents. Here, we have further tested the cerebral silence hypothesis by determining whether repeated exposures to isoflurane anesthesia reduce depressive-like symptoms or influence BDNF expression in male Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS), a model which is responsive to repeated electroconvulsive shocks (ECS, a model of ECT). Stress-susceptible, stress-resilient, and unstressed rats were exposed to 5 doses of isoflurane over a 15-day time period, with administrations occurring every third day. Isoflurane dosing is known to reliably produce rapid EEG burst-suppression (4% induction, 2% maintenance; 15 min). Antidepressant and anxiolytic effects of isoflurane were assessed after the first, third, and fifth drug exposure by measuring sucrose consumption, as well as performance on the open field and the elevated plus maze tasks. Tissue samples from the medial prefrontal cortex and hippocampus were collected, and levels of BDNF (brain-derived neurotrophic factor) protein were assessed. We find that isoflurane anesthesia had no impact on the behavior of stress-resilient or anhedonic rats in selected tests; findings which were consistent-perhaps inherently related-with unchanged levels of BDNF.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/prevenção & controle , Isoflurano/farmacologia , Estresse Psicológico/prevenção & controle , Anestésicos Inalatórios , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Eletroconvulsoterapia/métodos , Eletroencefalografia , Eletrochoque/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Isoflurano/administração & dosagem , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Wistar , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia
20.
Mol Pharmacol ; 98(3): 185-191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32580996

RESUMO

Several general anesthetics (GAs) produce pain or irritation upon administration, and this occurs predominantly through the activation of the nociceptive ion channel, transient receptor potential ankyrin type 1 (TRPA1). However, the effects of GAs on agonist-mediated TRPA1 activity are unclear. Here we show that a diverse range of noxious and non-noxious volatile anesthetics, at clinically relevant concentrations, inhibit ligand-activated TRPA1 currents. These effects are species-specific; GAs blocks rodent TRPA1 without affecting the Drosophila ortholog. Furthermore, propofol inhibits rodent but not human TRPA1. Analysis of chimeric TRPA1 proteins and mutagenesis combined reveals two amino acid residues located in the S5 domain, Ser876 and Thr877, that are critical for the inhibitory effects of isoflurane and propofol. Introduction of these residues into Drosophila TRPA1 confers anesthetic inhibition. Furthermore, several residues lining the presumptive binding pocket for noxious GAs are not required for the inhibitory effects of GAs. We conclude that anesthetics inhibit TRPA1 by interacting at a site distinct from the activation site. The inhibitory effects of GAs at TRPA1 may contribute to the diverse pharmacological action of these drugs. SIGNIFICANCE STATEMENT: We show that both noxious and non-noxious general anesthetics inhibit agonist-evoked transient receptor potential ankyrin type 1 (TRPA1) activity and identify critical amino acid residues located in the pore domain. Inhibition of TRPA1 may affect pain and vascular signaling during anesthesia.


Assuntos
Hipnóticos e Sedativos/farmacologia , Mutação , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Animais , Drosophila melanogaster , Células HEK293 , Humanos , Isoflurano/farmacologia , Camundongos , Propofol/farmacologia , Domínios Proteicos , Ratos , Especificidade da Espécie , Canal de Cátion TRPA1/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...