RESUMO
Ketogenesis, inferred by the production of acetoacetate plus ss-hydroxybutyrate, in isolated perfused livers from 24-h fasted diabetic rats submitted to short-term insulin-induced hypoglycemia (IIH) was investigated. For this purpose, alloxan-diabetic rats that received intraperitoneal regular insulin (IIH group) or saline (COG group) injection were compared. An additional group of diabetic rats which received oral glucose (gavage) (100 mg kg(-1)) 15 min after insulin administration (IIH + glucose group) was included. The studies were performed 30 min after insulin (1.0 U kg(-1)) or saline injection. The ketogenesis before octanoate infusion was diminished (p < 0.05) in livers from rats which received insulin (COG vs. IIH group) or insulin plus glucose (COG vs. IIH + glucose group). However, the liver ketogenic capacity during the infusion of octanoate (0.3 mM) was maintained (COG vs. IIH group and COG vs. IIH + glucose group). In addition, the blood concentration of ketone bodies was not influenced by the administration of insulin or insulin plus glucose. Taken together, the results showed that inspite the fact that insulin and glucose inhibits ketogenesis, livers from diabetic rats submitted to short-term IIH which received insulin or insulin plus glucose showed maintained capacity to produce acetoacetate and ss-hydroxybutyrate from octanoate.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Hipoglicemia/induzido quimicamente , Insulina/administração & dosagem , Corpos Cetônicos/biossíntese , Fígado/metabolismo , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Animais , Glicemia/análise , Caprilatos/administração & dosagem , Jejum , Glucose/administração & dosagem , Glucose/metabolismo , Injeções Intraperitoneais , Masculino , Perfusão , Ratos , Ratos WistarRESUMO
PURPOSE: To evaluate the in vivo alterations on ketone bodies metabolism after cerebral ischemia/reperfusion through an experimental model of brain ischemia induced by simple occlusion of common carotid arteries (CCAs) in Wistar rats. METHODS: Forty-eight male Wistar rats were randomly distributed on two groups (S - Sham; T - Test) and further redistributed into four times sets of study. After bilateral occlusion of CCAs for 30min, the animals of group T were allowed reperfusion for 0, 5, 10 and 15min. Samples of cerebral tissue and systemic arterial blood were collected and the metabolites acetoacetate (ACT) and beta-hydroxybutyrate (BHB) were determined. RESULTS: Cerebral ACT and BHB levels increased significantly in Group T after 30min of carotid occlusion (time 0). The highest brain ketone bodies (ACT+BHB) concentration was verified at 5min of reperfusion, decreasing after 10min of recirculation. Systemic ketone bodies levels increased similarly between test and sham groups. Group S demonstrated a significant increase in cerebral and systemic ACT and BHB concentrations mainly after 40-45min of study. CONCLUSIONS: The partial transient acute global brain ischemia induced by the bilateral carotid occlusion in Wistar rats triggered ketogenesis probably due to a central stimulation of catecholamine secretion. There was an increased cerebral uptake of ketone bodies following brain ischemia, reaffirming these metabolites as alternative energy substrates under conditions of cerebral metabolic stress as well as its potential role on neuroprotection. The greatest changes in ketone bodies metabolism were verified at initial minutes of recirculation as a result of the reperfusion injury phenomenon.
OBJETIVO: Avaliar as alterações in vivo no metabolismo dos corpos cetônicos após isquemia/reperfusão cerebral através de um modelo experimental de isquemia cerebral induzido pela simples oclusão das artérias carótidas comuns (CCAs) em ratos Wistar. MÉTODOS: Quarenta e oito ratos Wistar machos foram distribuídos aleatoriamente em dois grupos (S - Controle; T - Teste) e cada um deles redistribuídos em quatro tempos de estudos. Após oclusão bilateral das CCAs por 30min, permitiu-se reperfusão aos animais do grupo T nos tempos 0, 5, 10 e 15min. Foram coletadas amostras de tecido cerebral e sangue arterial sistêmico e quantificados os metabólitos acetoacetato (ACT) e beta-hidroxibutirato (BHB). RESULTADOS: Os níveis cerebrais de ACT e BHB aumentaram significantemente no Grupo T após 30min de oclusão carotídea (tempo 0). A maior concentração de corpos cetônicos (ACT+BHB) foi verificada aos 5min de reperfusão, diminuindo após 10min de recirculação. Os níveis de corpos cetônicos sistêmicos aumentaram de modo semelhante entre os grupos teste e controle. O Grupo S demonstrou significante aumento nas concentrações sistêmicas e cerebrais de ACT e BHB principalmente após 40-45min de estudo. CONCLUSÕES: A isquemia cerebral aguda transitória e parcial induzida pela oclusão bilateral das carótidas em ratos Wistar ativou a cetogênese provavelmente devido à estimulação central da secreção de catecolaminas. Houve um aumento da captação dos corpos cetônicos após isquemia cerebral, reafirmando esses metabólitos como substratos energéticos alternativos em condições de estresse metabólico cerebral, bem como suas potencialidades na neuroproteção. As maiores alterações no metabolismo dos corpos cetônicos foram verificadas nos minutos iniciais de recirculação como resultado do fenômeno da lesão de reperfusão.
Assuntos
Animais , Masculino , Ratos , Isquemia Encefálica/metabolismo , Artéria Carótida Primitiva , Doenças das Artérias Carótidas/fisiopatologia , Corpos Cetônicos/metabolismo , Traumatismo por Reperfusão/metabolismo , /sangue , Acetoacetatos/sangue , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
PURPOSE: To evaluate the in vivo alterations on ketone bodies metabolism after cerebral ischemia/reperfusion through an experimental model of brain ischemia induced by simple occlusion of common carotid arteries (CCAs) in Wistar rats. METHODS: Forty-eight male Wistar rats were randomly distributed on two groups (S - Sham; T - Test) and further redistributed into four times sets of study. After bilateral occlusion of CCAs for 30 min, the animals of group T were allowed reperfusion for 0, 5, 10 and 15 min. Samples of cerebral tissue and systemic arterial blood were collected and the metabolites acetoacetate (ACT) and beta-hydroxybutyrate (BHB) were determined. RESULTS: Cerebral ACT and BHB levels increased significantly in Group T after 30 min of carotid occlusion (time 0). The highest brain ketone bodies (ACT+BHB) concentration was verified at 5 min of reperfusion, decreasing after 10 min of recirculation. Systemic ketone bodies levels increased similarly between test and sham groups. Group S demonstrated a significant increase in cerebral and systemic ACT and BHB concentrations mainly after 40-45 min of study. CONCLUSIONS: The partial transient acute global brain ischemia induced by the bilateral carotid occlusion in Wistar rats triggered ketogenesis probably due to a central stimulation of catecholamine secretion. There was an increased cerebral uptake of ketone bodies following brain ischemia, reaffirming these metabolites as alternative energy substrates under conditions of cerebral metabolic stress as well as its potential role on neuroprotection. The greatest changes in ketone bodies metabolism were verified at initial minutes of recirculation as a result of the reperfusion injury phenomenon.
Assuntos
Isquemia Encefálica/metabolismo , Doenças das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva , Corpos Cetônicos/metabolismo , Traumatismo por Reperfusão/metabolismo , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Animais , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Masculino , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
RACIONAL: Transplante de fígado é inevitavelmente associado com períodos de isquemia completa. No entanto, o tempo de oclusão do pedículo hepático é limitado pelas conseqüências da injúria pós-isquêmica do fígado. OBJETIVO: Determinar as principais alterações metabólicas ocasionadas pela isquemia hepática e a provável ação hepatoprotetora da ciclosporina. MÉTODOS: Isquemia hepática normotérmica por 60 minutos foi induzida em ratos. Em seguida, as alterações com o tempo (0, 1, 6, 24 horas) das concentrações sangüíneas e hepáticas de lactato, piruvato, glicose, corpos cetônicos e razão acetoacetato/3-hidroxibutirato, bem como o estado redox citoplasmático e mitocondrial do tecido hepático foram determinados. Outro grupo de animais foi pré-tratado com ciclosporina (10 mg/kg), sendo estudadas as alterações metabólicas no tempo 1 hora após revascularização hepática. RESULTADOS: A isquemia hepática causou elevação da concentração de lactato no fígado, sugerindo que pronunciado grau de metabolismo anaeróbico ocorreu durante o período de isquemia. Isquemia hepática acarretou ainda queda da concentração e da razão dos corpos cetônicos (acetoacetato/3-hidroxibutirato) no sangue arterial no tempo de 1 hora após revascularização. Tal fato reflete que a injuria isquêmica do fígado interfere na cetogênese. CONCLUSAO: O tratamento com ciclosporina causa elevação das concentrações dos corpos cetônicos e da razão acetoacetato/3-hidroxibutirato no sangue arterial após 1 hora de reperfusão hepática, sugerindo que esta droga acelera a cetogênese e, conseqüentemente, a recuperação da lesão isquêmica do fígado.
Assuntos
Animais , Masculino , Ratos , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Isquemia/metabolismo , Fígado/irrigação sanguínea , /sangue , /metabolismo , Acetoacetatos/sangue , Acetoacetatos/metabolismo , Hepatectomia , Isquemia/sangue , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Transplante de Fígado , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos WistarRESUMO
Glucose is the main substrate that fulfills energy brain demands. However, in some circumstances, such as diabetes, starvation, during the suckling period and the ketogenic diet, brain uses the ketone bodies, acetoacetate and beta-hydroxybutyrate, as energy sources. Ketone body utilization in brain depends directly on its blood concentration, which is normally very low, but increases substantially during the conditions mentioned above. Glutamate neurotoxicity has been implicated in neurodegeneration associated with brain ischemia, hypoglycemia and cerebral trauma, conditions related to energy failure, and to elevation of glutamate extracellular levels in brain. In recent years substantial evidence favoring a close relation between glutamate neurotoxic potentiality and cellular energy levels, has been compiled. We have previously demonstrated that accumulation of extracellular glutamate after inhibition of its transporters, induces neuronal death in vivo during energy impairment induced by glycolysis inhibition. In the present study we have assessed the protective potentiality of the ketone body, acetoacetate, against glutamate-mediated neuronal damage in the hippocampus of rats chronically treated with the glycolysis inhibitor, iodoacetate, and in hippocampal cultured neurons exposed to a toxic concentration of iodoacetate. Results show that acetoacetate efficiently protects against glutamate neurotoxicity both in vivo and in vitro probably by a mechanism involving its role as an energy substrate.
Assuntos
Acetoacetatos/farmacologia , Glicólise/efeitos dos fármacos , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acetoacetatos/sangue , Trifosfato de Adenosina/análise , Trifosfato de Adenosina/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Ácidos Dicarboxílicos/efeitos adversos , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Esquema de Medicação , Interações Medicamentosas , Embrião de Mamíferos , Inibidores Enzimáticos/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ácido Glutâmico/farmacologia , Hipocampo/efeitos dos fármacos , Iodoacetatos/efeitos adversos , Masculino , Fármacos Neuroprotetores/sangue , Inibidores da Captação de Neurotransmissores/efeitos adversos , Gravidez , Pirrolidinas/efeitos adversos , Ácido Pirúvico/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Alcohol ingestion decreases plasma free fatty acids (FFAs) and lipid oxidation. This study was conducted to determine palmitate turnover in alcoholics during a short abstinence period and after an ethanol load and in a group of nonalcoholic control subjects, looking for correlations between palmitate turnover, FFA, acetate, and acetoacetate/beta hydroxybutyrate ratio (AKBR). Palmitate C14 turnover was studied in five alcoholics during early abstinence and after a 0.8 g/kg ethanol load, and in five nonalcoholic normal controls. Plasma levels of FFA, acetate, acetoacetate, and beta hydroxybutyrate were measured before and during the ethanol load. A needle hepatic biopsy was performed in alcoholics. FFA levels, palmitate flux, oxidation, and nonoxidative disposal were similar in alcoholics compared with control subjects, decreasing significantly after the ethanol load in both groups. AKBR and ketone bodies were similar in both groups in the basal period. After the alcohol infusion, AKBR decreased significantly. Acetoacetate levels did not change, and beta hydroxybutyrate and total ketone bodies increased significantly in alcoholics and control subjects. A positive correlation was found between FFA levels and palmitate flux. Liver biopsies showed mild changes in the patients studied. The similar inhibition of lipid turnover, FFA release, and the drop in AKBR observed after an alcohol load in alcoholics and control subjects suggest that this effect is mediated by alcohol metabolism and not by metabolic alterations present in alcoholics.
Assuntos
Alcoolismo/sangue , Etanol/administração & dosagem , Lipídeos/sangue , Ácido 3-Hidroxibutírico , Acetatos/sangue , Acetoacetatos/sangue , Adulto , Alcoolismo/patologia , Biópsia por Agulha , Etanol/sangue , Ácidos Graxos não Esterificados/sangue , Humanos , Hidroxibutiratos/sangue , Corpos Cetônicos/sangue , Cinética , Fígado/patologia , Taxa de Depuração Metabólica , Ácido Palmítico/sangueRESUMO
1. The concentrations of acetoacetate and 3-hydroxybutyrate have been determined in the blood of the green lizard Ameiva ameiva (Teiidae) in fed animals and in animals starved for periods from one week to about four months. 2. The concentrations of acetoacetate are low and unaltered in fed and starved animals, being in the range from 0.014 to 0.018 mM. 3. The concentrations of 3-hydroxybutyrate are high: 2.67 mM, in fed animals, falling during starvation down to 0.26 mM. 4. The 3-hydroxybutyrate/acetoacetate ratio is high, 151, in fed animals, falling down to 17. 5. The possible importance of ketone bodies in the metabolism of Ameiva ameiva is discussed.
Assuntos
Corpos Cetônicos/sangue , Lagartos/fisiologia , Ácido 3-Hidroxibutírico , Acetoacetatos/sangue , Animais , Hidroxibutiratos/sangue , Valores de Referência , Inanição , Fatores de TempoRESUMO
A female child presented at one year of age with a febrile illness and loose stools, then developed severe ketoacidosis with vomiting; an apparent salicylate level of 11 mg/dl was measured. A sibling had died in similar circumstances nine years earlier. Investigation revealed that the child did not have salicylate intoxication, and that high levels of acetoacetate in blood and urine were giving readings indicative of the presence of salicylate on routine testing. Gas-liquid chromatographic analysis combined with mass spectrometry on urine samples revealed the presence of 2-methyl-acetoacetate, 2-methyl-3-hydroxybutyrate, and tiglyl glycine in appreciable amounts, indicating a defect in isoleucine catabolism located at the beta-ketothiolase step. The oxidation of 14C-isoleucine to CO2 in cultured fibroblasts confirmed that this pathway was defective. We present evidence that beta-ketothiolase deficiency is not simply a defect of isoleucine degradation; the deficient enzyme is the K+ dependent short-chain mitochondrial thiolase, which also plays a major catalytic role in ketone body and fatty acid oxidation.