RESUMO
The purpose of the present work was to verify if tadalafil affects hepatic glucose output, one of the primary targets of cAMP, in the isolated perfused rat liver. No effects on glycogen catabolism and oxygen uptake were found under basal conditions for tadalafil concentrations in the range between 0.25 and 10 µM. However, tadalafil had a clear and time-dependent inhibitory effect on the cAMP- and glucagon-stimulated glucose release. Constant infusion of tadalafil in the range between 0.25 and 10 µM eventually abolished 100% of the stimulatory action of those effectors. The tadalafil concentrations producing half-maximal rates of inhibition of the cAMP and glucagon stimulated glycogenolysis were 0.46±0.04 and 1.07±0.16 µM, respectively. These concentrations are close to the plasma peak concentrations in patients after ingestion of 20 mg tadalafil. The drug also diminished the activity of glycogen phosphorylase a and increased the activities of glucose 6-phosphatase, glucokinase, pyruvate kinase and glucose 6-phosphate dehydrogenase. These actions occurred only in the cellular environment. Tadalafil did not affect binding of cAMP to protein kinase A. Diminution of cAMP-stimulated glucose output is the opposite of what can be expected from a phosphodiesterase inhibition, the most common effect attributed to tadalafil. Diminution of glucose output by tadalafil can be attributed (a) to an interference with glycogen phosphorylase stimulation and (b) to an increased futile cycling of glucose 6-phosphate and glucose with a concomitant increased flow of hexose units into cellular metabolic pathways. The effects described in the present work may prove to represent important side effects of tadalafil.
Assuntos
Carbolinas/farmacologia , AMP Cíclico/antagonistas & inibidores , Glucose/metabolismo , Fígado/efeitos dos fármacos , Animais , Bioensaio , Glucagon/metabolismo , Fígado/enzimologia , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Ratos , Tadalafila , Fatores de TempoRESUMO
Dysfunction of the mitochondrial respiratory chain and increased oxidative stress is a striking phenomenon in the brain of aged individuals. For this reason there has been a constant search for drugs and natural products able to prevent or at least to mitigate these problems. In the present study the effects of an aqueous extract of Agaricus blazei, a medicinal mushroom, on the oxidative state and on the functionality of mitochondria from the brain of old rats (21 months) were conducted. The extract was administered intragastrically during 21 days at doses of 200 mg/kg. The administration of the A. blazei extract was protective to the brain of old rats against oxidative stress by decreasing the lipid peroxidation levels and the reactive oxygen species content and by increasing the nonenzymic and enzymic antioxidant capacities. Administration of the A. blazei extract also increased the activity of several mitochondrial respiratory enzymes and, depending on the substrate, the mitochondrial coupled respiration.
Assuntos
Agaricus/química , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Agaricus/metabolismo , Envelhecimento , Animais , Antioxidantes/química , Encéfalo/enzimologia , Encéfalo/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Oxirredutases/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Água/químicaRESUMO
Citrus aurantium extracts, which contain large amounts of p-synephrine, are widely used for weight loss purposes and as appetite suppressants. In the liver, C. aurantium (bitter orange) extracts affect hemodynamics, carbohydrate metabolism, and oxygen uptake. The purpose of the present work was to quantify the action of p-synephrine and also to obtain indications about its mechanism of action, a task that would be difficult to accomplish with C. aurantium extracts due to their rather complex composition. The experimental system was the isolated perfused rat liver. p-Synephrine significantly stimulated glycogenolysis, glycolysis, gluconeogenesis, and oxygen uptake. The compound also increased the portal perfusion pressure and the redox state of the cytosolic NAD(+)/NADH couple. A Ca(2+)-dependency for both the hemodynamic and the metabolic effects of p-synephrine was found. p-Synephrine stimulated both cAMP overflow and the initial Ca(2+) release from the cellular stores previously labeled with (45)Ca(2+). The metabolic and hemodynamic actions of p-synephrine were strongly inhibited by α-adrenergic antagonists and moderately affected by ß-adrenergic antagonists. The results allow to conclude that p-synephrine presents important metabolic and hemodynamic effects in the liver. These effects can be considered as both catabolic (glycogenolysis) and anabolic (gluconeogenesis), they are mediated by both α- and ß-adrenergic signaling, require the simultaneous participation of both Ca(2+) and cAMP, and could be contributing to the overall stimulation of metabolism that usually occurs during weight loss periods.
Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Fígado/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Sinefrina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Cálcio/metabolismo , Citrus/metabolismo , AMP Cíclico/biossíntese , Gluconeogênese/efeitos dos fármacos , Glicogenólise/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Extratos Vegetais/farmacologia , Prazosina/farmacologia , Propanolaminas/farmacologia , Propranolol/farmacologia , Ácido Pirúvico/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Ioimbina/farmacologiaRESUMO
The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate), as revealed by the increase in ¹4CO2 production derived from ¹4C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the ß-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.
Assuntos
Caprilatos/metabolismo , Hemodinâmica/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Octopamina/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/química , Depressores do Apetite/farmacologia , Citrus/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Octopamina/química , Octopamina/farmacologia , Oxirredução/efeitos dos fármacos , RatosRESUMO
Adjuvant-induced arthritis is an experimental immunopathology in rats that is often used as a model for studying autoimmune chronic inflammation and inflammatory cachexia. In these animals oxidative stress is quite pronounced in the articular inflammation sites. The purpose of this study was to evaluate oxidative stress in the liver of arthritic rats in which morphological and metabolic alterations have been reported to occur. Oxidative injury parameters, levels and production of reactive oxygen species (ROS), and antioxidant parameters were measured in the total liver homogenate and in subcellular fractions, namely cytosol, mitochondria, and peroxisomes. Arthritic rats presented higher levels of ROS than controls in the total homogenate (46% higher) and in all subcellular fractions (51, 38, and 55% higher for mitochondria, peroxisome, and cytosol, respectively). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (75%) and in all subcellular fractions (189, 227, and 260%, respectively, for mitochondria, peroxisomes, and cytosol). The TBARS levels of arthritic rats were more elevated in the total homogenate (36%), mitochondria (20%), and peroxisomes (16%). Arthritic rats also presented higher levels of NO markers in the peroxisomes (112%) and in the cytosol (35%). The catalase activity of all cell compartments was strongly diminished (between 77 and 87%) by arthritis, and glutathione peroxidase activities were diminished in the mitochondria (33.7%) and cytosol (41%). The cytosolic glucose-6-phosphate dehydrogenase activity, on the other hand, was increased (62.9%), the same happening with inducible peroxisomal NO synthase (119.3%). The superoxide dismutase and glutathione reductase activities were not affected. The GSH content was diminished by arthritis in all cellular compartments (50 to 59% diminution). The results reveal that the liver of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and that, in consequence, injury to lipids and proteins is highly significant. The higher ROS content of the liver of arthritic rats seems to be the consequence of both a stimulated pro-oxidant system and a deficient antioxidant defense with a predominance of the latter as indicated by the strongly diminished activities of catalase and glutathione peroxidase.
Assuntos
Artrite Experimental/metabolismo , Adjuvante de Freund/administração & dosagem , Inflamação/metabolismo , Estresse Oxidativo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Caquexia/induzido quimicamente , Caquexia/metabolismo , Caquexia/patologia , Citosol/efeitos dos fármacos , Citosol/metabolismo , Citosol/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Peroxissomos/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite supressants. An important fruit component is p-synephrine, which is structurally similar to the adrenergic agents. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of the C. aurantium extract on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways, including oxygen uptake and perfusion pressure. The C. aurantium extract and p-synephrine increased glycogenolysis, glycolysis, oxygen uptake and perfusion pressure. These changes were partly sensitive to α- and ß-adrenergic antagonists. p-Synephrine (200 µM) produced an increase in glucose output that was only 15% smaller than the increment caused by the extract containing 196 µM p-synephrine. At low concentrations the C. aurantium extract tended to increase gluconeogenesis, but at high concentrations it was inhibitory, opposite to what happened with p-synephrine. The action of the C. aurantium extract on liver metabolism is similar to the well known actions of adrenergic agents and can be partly attributed to its content in p-synephrine. Many of these actions are catabolic and compatible with the weight-loss effects usually attributed to C. aurantium.
Assuntos
Citrus/química , Frutas/química , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sinefrina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Suplementos Nutricionais , Glicogênio/metabolismo , Glicogenólise , Glicólise , Fígado/metabolismo , Técnicas de Cultura de Órgãos , Consumo de Oxigênio/efeitos dos fármacos , Perfusão , Ratos , Redução de Peso/efeitos dos fármacosRESUMO
Bentazon removal by Ganoderma lucidum cultured in liquid and solid state conditions was compared in this work. In solid state cultures, the fungus produced both ligninolytic enzymes, namely laccase and Mn peroxidase. In liquid cultures, the main ligninolytic enzyme produced was laccase. In both types of cultures bentazon improved the production of laccase without significant alteration in the production of Mn peroxidase. In solid state cultures, where high levels of both laccase and Mn peroxidase activities were found, the fungus was more resistant to the action of the herbicide (50 mM in solid state cultures against 20 mM in liquid cultures) and more efficient in removing bentazon (90% removal against 55% in liquid cultures after 10 days of cultivation). Furthermore, the solid state culture filtrates were more efficient in the in vitro degradation of bentazon than the liquid culture filtrates. These observations suggest that both enzymes, laccase and Mn peroxidase, are involved in bentazon degradation. The results further suggest that solid state cultures of Ganoderma lucidum could be useful in strategies designed to reduce environmental contamination by bentazon.