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OBJECTIVES: To identify and describe functional urinary symptoms, uro-nephrological complications and their impact on quality of life in a cohort of patients diagnosed with the Wolfram syndrome (SW). PATIENTS AND METHODS: A transversal descriptive patient's cohort study was performed. The Urinary Symptom Profile (USP) and the International Consultation Incontinence Questionnaire - Female Lower Urinary Tracts Symptoms (ICIQ-FLUTS) were used to evaluate urinary symptoms and their impact on quality of life through direct interviews conducted by telephone. A less than 6-month old renal ultrasound and serum creatinine results were asked to the patient or physician. RESULTS: Thirty-three patients have been contacted and 22 (73%) agreed to participate in this study. Eighteen patients over 22 had spontaneous micturition when four of them had an urinary diversion (two definitive, two temporaries) before being included in this study. Seventy-three percent of patients with spontaneous micturition had urinary symptoms. A severe or moderate symptoms score was noted in 67% (12/18 patients) and 11% (2/18 patients) respectively. CONCLUSION: Functional urinary dysfunctions were frequent and impacted quality of life in more than one half of patients diagnosed with SW in this study. Early diagnostic and regular urological follow-up can improve the quality of life and prevent severe urinary complications.
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Enfermedades Urológicas/etiología , Síndrome de Wolfram/complicaciones , Adolescente , Adulto , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Calidad de Vida , Enfermedades Urológicas/psicología , Adulto JovenRESUMEN
OBJECTIVE: The objective of our study was to describe and evaluate the prevalence of chronic pain in persons with Charcot-Marie-Tooth (CMT) disease during a multidisciplinary consultation at the Center of Reference for Neuromuscular Diseases. METHODOLOGY: This prospective study was conducted between 2008 and 2010, it was a partnership between a Center of Reference for Neuromuscular Diseases (Centre de référence des maladies neuromusculaires [CRMD]) and a Department for the Assessment and Treatment of Pain (Département d'évaluation et de traitement de la douleur [DETD]). The evaluation consisted in a complete assessment of each patient during the first multidisciplinary consultation, with a previously established diagnosis validated by genetic testing, by various specialists: neurologist, PM&R physician, pain management specialist and physiotherapist. The evaluation tools used were Visual Analogical Scale (VAS), Hospital Anxiety and Depression Scale (HAD), DN4 scale, Neuropathic Pain Symptom Inventory (NPSI) (if DN4≥4), Pain Questionnaire of Saint Antoine (QDSA) (if DN4<4), body representation to define the painful areas, Overall Neuropathy Limitations Scale (ONLS), Medical Research Council scale (MRC), Short Questionnaire on Pain (QCD), VAS during transfers, self-care, getting dressed and physiotherapy sessions and quantified use of analgesics. RESULTS: A total of 50 patients were included (28 women, 22 men); two patients (one man and one woman) were discarded from the study because of missing pain assessment data. Mean age was 47years (R: 14-85), in average the symptoms had been present for the past 20years (R: 0.3-68), most patients had little impairment, the mean MRC was 53 (R: 36-60), with CMT1A being predominant (CMT1A: 76.9%, CMTX: 13.5%, CMT2: 5.8%, CMT4: 3.8%). It is noted that 65.4% of patients reported some pain with a mean duration of pain at 140months (R: 5-660). The mean VAS was 5.5 (R: 1-10), greater than 4 in 79.4% of cases, requiring the use of analgesics in 38.4% of cases (step 1: 60%, step 2: 40% on the WHO pain relief ladder). The predominant location of the pain was distal, peripheral and symmetric (64.7%); furthermore the feet were affected in 80% of cases. DN4 was positive in 40.6% of painful patients. In 62.5% of the cases, the pain did not have an underlying mechanical origin. The emotional impact remained quite modest (HAD: A=8; D=5). Patients with CMT1A seemed less affected by pain (P=0.03). CONCLUSION: This original study describes the pain in patients with CMT disease during a primary multidisciplinary consultation. We see that in 66% of cases, patients do report some pain, this pain is usually moderate, preferentially located in the extremities and is symmetric. In 62.5% of cases, the pain has a neuromuscular origin with a positive DN4 in 50% of cases in this etiology. In our study, patients with CMT1A report less pain than patients with other CMT types. This disease being quite rare (rare disease), the number of patients did not allow us to bring up statistically significant results. The pain must be thoroughly screened for because of its frequency in persons with CMT.
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Enfermedad de Charcot-Marie-Tooth/complicaciones , Dolor Crónico/etiología , Dimensión del Dolor , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Charcot-Marie-Tooth/clasificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVES: To assess French district nurses' opinions towards euthanasia and to study factors associated with these opinions, with emphasis on attitudes towards terminal patients. DESIGN AND SETTING: An anonymous telephone survey carried out in 2005 among a national random sample of French district nurses. PARTICIPANTS: District nurses currently delivering home care who have at least 1 year of professional experience. Of 803 district nurses contacted, 602 agreed to participate (response rate 75%). MAIN OUTCOME MEASURES: Opinion towards the legalisation of euthanasia (on a five-point Likert scale from "strongly agree" to "strongly disagree"), attitudes towards terminal patients (discussing end-of-life issues with them, considering they should be told their prognosis, valuing the role of advance directives and surrogates). RESULTS: Overall, 65% of the 602 nurses favoured legalising euthanasia. Regarding associated factors, this proportion was higher among those who discuss end-of-life issues with terminal patients (70%), who consider competent patients should always be told their prognosis (81%) and who value the role of advance directives and surrogates in end-of-life decision-making for incompetent patients (68% and 77% respectively). Women and older nurses were less likely to favour legalising euthanasia, as were those who believed in a god who masters their destiny. CONCLUSIONS: French nurses are more in favour of legalising euthanasia than French physicians; these two populations contrast greatly in the factors associated with this support. Further research is needed to investigate how and to what extent such attitudes may affect nursing practice and emotional well-being in the specific context of end-of-life home care.
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Actitud del Personal de Salud , Eutanasia/ética , Servicios de Atención de Salud a Domicilio/ética , Relaciones Enfermero-Paciente/ética , Cuidado Terminal/ética , Enfermería en Salud Comunitaria , Eutanasia/psicología , Francia , Humanos , Análisis Multivariante , Encuestas y CuestionariosRESUMEN
We studied the influence of nitric oxide (NO) endogenously produced by adipocytes in lipolysis regulation. Diphenyliodonium (DPI), a nitric oxide synthase (NOS) inhibitor, was found to completely suppress NO synthesis in intact adipocytes and was thus used in lipolysis experiments. DPI was found to decrease both basal and dibutyryl cAMP (DBcAMP)-stimulated lipolysis. Inhibition of DBcAMP-stimulated lipolysis by DPI was prevented by S-nitroso-N-acetyl-penicillamine (SNAP), a NO donor. This antilipolytic effect of DPI was also prevented by two antioxidants, ascorbate or diethyldithiocarbamic acid (DDC). Preincubation of isolated adipocytes with DPI (30 min) before exposure to DBcAMP almost completely abolished the stimulated lipolysis. Addition of SNAP or antioxidant during DPI preincubation restored the lipolytic response to DBcAMP, whereas no preventive effects were observed when these compounds were added simultaneously to DBcAMP. Exposure of isolated adipocytes to an extracellular generating system of oxygen species (xanthine/xanthine oxidase) or to H(2)O(2) also resulted in an inhibition of the lipolytic response to DBcAMP. H(2)O(2) or DPI decreased cAMP-dependent protein kinase (PKA) activation. The DPI effect on PKA activity was prevented by SNAP, ascorbate, or DDC. These results provide clear evidence that 1) the DPI antilipolytic effect is related to adipocyte NOS inhibition leading to PKA alterations, and 2) endogenous NO is required for the cAMP lipolytic process through antioxidant-related effect.
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Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Antioxidantes/farmacología , Lipólisis/fisiología , Óxido Nítrico/fisiología , Animales , Compuestos de Bifenilo/farmacología , Bucladesina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Peróxido de Hidrógeno/farmacología , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Compuestos Onio/farmacología , Oxidantes/farmacología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Obesity is a major cause of human essential hypertension and there are clear evidences that abnormal kidney functions play a key role in obesity hypertension. Feeding rats a cafeteria diet has been extensively used as an experimental model to study obesity and energy balance expenditure. The present study investigated whether rats fed a cafeteria diet develop hypertension with alterations in renal alpha2-adrenoceptor subtype distribution. Weight gain induced by feeding rats a cafeteria diet during 8 weeks was associated with a marked increase in blood pressure. Insulin levels were higher in these hypertensive rats, leading to a decreased plasma glucose/insulin ratio. Based on radioligand-binding studies using [3H]-RX821002 and selective competitors, a raise in alpha2-adrenoceptor density that was solely due to an increased alpha2B-adrenoceptor subtype density was detected in the kidney of the cafeteria-fed rat. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) experiments showed an overexpression of the gene encoding the alpha2B-adrenoceptor subtype in these rats. On the other hand, despite a similar mRNA level, the alpha2A-adrenoceptor subtype was no more detectable by radioligand-binding studies in the kidney of the cafeteria-fed rat. In conclusion, cafeteria-fed rats are hypertensive, with renal alterations in alpha2-adrenoceptor distribution. These alterations, which are not related to genetic factors, may play a key role in the onset of hypertension.
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Dieta/efectos adversos , Hipertensión/etiología , Riñón/metabolismo , ARN Mensajero/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Animales , Biomarcadores , Presión Sanguínea , Predisposición Genética a la Enfermedad , Hipertensión/genética , Hipertensión/metabolismo , Masculino , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
1. Possible nitric oxide (NO)-mediated effects on lipolysis were investigated in vivo in human subcutaneous adipose tissue using microdialysis, as well as in vitro on isolated fat cells of non-obese, healthy volunteers. NO donors were added to the ingoing dialysate solvents. 2. Changes in lipolysis and local blood flow were investigated by measuring glycerol levels and ethanol ratios, respectively, in the microdialysates. 3. It was shown that the NO synthase inhibitor, N(G)-monomethyl L-arginine (L-NMMA), but not the biologically inactive enantiomer N(G)-monomethyl D-arginine (D-NMMA), increased glycerol levels in the microdialysates without causing a change of local blood flow. In addition, L-NMMA increased glycerol levels in the microdialysate when local blood flow was stimulated with hydralazine. 4. Nitric oxide gas as well as the NO donor, nitroglycerine, reduced glycerol release from isolated adipocytes in vitro. 5. Expression of inducible nitric oxide synthase (iNOS) in human adipose tissue was shown by Western blot analysis. Biologically active NOS was demonstrated by measuring total enzymatic activity. 6. In conclusion, the data demonstrate that inhibition of NO release in subcutaneous adipose tissue results in an increased lipolysis in vivo. These effects, which were also observed in vitro, are independent of local blood flow changes. Furthermore, the demonstration of enzymatic NOS activity and the expression of inducible nitric oxide synthase (iNOS) in adipose tissue indicate that locally synthesized NO may play a role in the physiological control of lipolysis in human adipose tissue.
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Tejido Adiposo/metabolismo , Lipólisis , Óxido Nítrico/fisiología , Adulto , Femenino , Glicerol/metabolismo , Humanos , Hidralazina/farmacología , Masculino , Microdiálisis , Persona de Mediana Edad , omega-N-Metilarginina/farmacologíaRESUMEN
In isolated adipocytes, the nitrosothiols S-nitroso-N-acetyl-penicillamine (SNAP) and S-nitrosoglutathione stimulate basal lipolysis, whereas the nitric oxide (NO.) donor 1-propamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA-NONOate) or NO gas have no effect. The increase in basal lipolysis due to nitrosothiols was prevented by dithiothreitol but not by a guanylate cyclase inhibitor. In addition the cyclic GMP-inhibited low Km, cyclic AMP phosphodiesterase activity was inhibited by SNAP suggesting that SNAP acting as NO+ donor increases basal lipolysis through a S-nitrosylation mediated inhibition of phosphodiesterase. Contrasting with these findings, SNAP reduced both isoproterenol-stimulated lipolysis and cyclic AMP production, whereas it failed to modify forskolin-, dibutyryl cyclic AMP-, or isobutylmethylxanthine-stimulated lipolysis, suggesting that SNAP interferes with the beta-adrenergic signal transduction pathway upstream the adenylate cyclase. In contrast with SNAP, PAPA-NONOate or NO gas inhibited stimulated lipolysis whatever the stimulating agents used without altering cyclic AMP production. Moreover PAPA-NONOate slightly reduces (30%) the hormone-sensitive lipase (HSL) activity indicating that stimulated lipolysis inhibition by NO. is linked to both inhibition of the HSL activity and the cyclic AMP-dependent activation of HSL. These data suggest that NO. or related redox species like NO+/NO- are potential regulators of lipolysis through distinct mechanisms.
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Tejido Adiposo/metabolismo , Óxido Nítrico/fisiología , Tejido Adiposo/citología , Células Cultivadas , GMP Cíclico/fisiología , Hidrazinas/química , Lipólisis , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Compuestos Nitrosos/química , Oxidación-Reducción , Penicilamina/análogos & derivados , Penicilamina/químicaRESUMEN
Nitric oxide synthase (NOS) activity was detected in soluble and membranous fractions of adipose tissue homogenates of control rats. After LPS-treatment, this activity was (i) markedly increased (about 10-fold) in both fractions, (ii) unaltered after dexamethasone pretreatment, (iii) partly calcium-calmodulin sensitive, and (iv) almost entirely accounted by the NOS activity found in isolated adipocytes. In adipose tissue homogenates from control rats, Western blot analysis demonstrated the presence of the endothelial (eNOS) isoform in the membranous fraction of control rats and of the inducible (iNOS) isoform in the soluble and membranous fractions. After LPS treatment, the amount of immunoreactive iNOS protein was dramatically increased, suggesting that adipose tissue is an important site of NO production during the endotoxic shock.
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Tejido Adiposo/enzimología , Óxido Nítrico Sintasa/metabolismo , Animales , Biopterinas/análogos & derivados , Biopterinas/farmacología , Western Blotting , Dexametasona/farmacología , Endotoxinas/farmacología , Inducción Enzimática/efectos de los fármacos , Glucocorticoides/farmacología , Isoenzimas/metabolismo , Lipopolisacáridos/farmacología , Hígado/enzimología , Masculino , Miocardio/enzimología , Ratas , Ratas Sprague-Dawley , Choque Séptico/fisiopatología , Fracciones Subcelulares/enzimologíaRESUMEN
The reactions of free radicals derived from ethanol metabolism with Cu,Zn SOD were studied. 1-Hydroxyethyl radicals were generated by gamma radiolysis of a N2O-saturated ethanolic solution (10(-2) M) in phosphate buffer (10(-3) M, pH 7.4). To generate acetyl radicals by gamma radiolysis, we used ethylene glycol (10(-2) M) in phosphate buffer (10(-3) M, pH 7.4). This allows us to avoid the use of acetaldehyde, which may be toxic toward various cellular constituents. We have previously reported that HO. radicals reacting with either acetaldehyde or ethylene glycol produce the same free radicals (Santiard et al., 1991, J. Chim. Phys. 88, 967-976). the rate constant reaction of 1-hydroxyethyl free radicals with Cu,Zn-SOD was measured separately by competition kinetics with the spin trapping agent alpha-(4-pyridyl 1-oxide) N-terbutylnitrone (4-POBN), after having measured the rate constant of scavenging of 1-hydroxyethyl free radicals by 4-POBN in the absence of SOD. We found k1 (4-POBN + 1-hydroxyethyl radical) = 4.2 10(5) M-1 s-1 and kR (SOD + 1-hydroxyethyl radical) = 6.8 10(5) M-1 s-1). 1-Hydroxyethyl or acetyl radicals produced dose-dependent Cu,Zn-SOD inactivation. The inactivation rate constant of Cu,Zn-SOD by 1-hydroxyethyl radicals is ki = 1.13 10(4) M-1 s-1. Free radicals derived from ethanol metabolism can thus react SOD leading to enzyme inactivation, besides the fact that the reactivities of 1-hydroxyethyl radicals with 4-POBN and with proteins such as Cu,Zn SOD are of the same order of magnitude could explain the difficulties to trap in vivo these radicals.
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Superóxido Dismutasa/antagonistas & inhibidores , Animales , Unión Competitiva , Bovinos , Radioisótopos de Cobalto , Etanol/metabolismo , Radicales Libres , Rayos gamma , Radical Hidroxilo/química , Radical Hidroxilo/farmacología , Cinética , Óxidos de Nitrógeno , Radiólisis de Impulso , Piridinas , Marcadores de SpinRESUMEN
The manganese superoxide dismutase plays an important role in the cellular response to oxidative stress and appears to be highly regulated by many factors. The study of this gene's expression is difficult to achieve due to multiple rat Mn-SOD transcripts. In this report we described the quantification of the rat Mn-SOD transcripts by competitive reverse transcription-polymerase chain reaction. The competitor RNA was transcribed from a synthetic gene generated by PCR. This gene was composed of the T7 polymerase promoter linked to a 102 base-pairs deleted rat Mn-SOD cDNA. Both the target RNA and the competitor RNA were reverse-transcribed and coamplified with the same primers. All the rat Mn-SOD mRNAs were simultaneously quantified by amplification of a common region. The use of a fluorescent primer led to fluorescent PCR products detected and quantified by the use of an automated DNA sequencer which avoides the use of the radioactivity. Small variations in Mn-SOD mRNA concentration (30%) were determined. This method has been applied to study the expression of Mn-SOD mRNA in rat liver after chronic ethanol feeding. Expression of Mn-SOD transcripts was not modified and did not account for the increased Mn-SOD activity.
RESUMEN
Functional characteristics of mitochondria isolated from liver, brain and heart were studied in ethanol-fed rats using ethanol administration in drinking water as a model of moderate alcohol intoxication. Our results show a slight decrease in liver cytochrome aa3 content, the mitochondrial alteration which is most consistently observed during chronic ethanol feeding. In liver and heart mitochondria, ethanol consumption led to an increase in state 3 respiration with NAD(+)-linked substrates, whereas no changes were apparent in respiration rates with succinate as substrate. However a decrease was found in state 3 respiration with succinate in brain mitochondria isolated from ethanol-fed rats. Submitochondrial particles (SMP) were used to study the superoxide radical (O2-.) production at the level of antimycin-inhibited regions of the respiratory chain. It appears that there is no clear correlation between ethanol effects on respiration and O2-. production. Whereas O2-. generation remained unchanged in heart mitochondria, an elevation of O2-. generation was observed in brain mitochondria, and in contrast, the rate of O2-. production was decreased in liver mitochondria of the ethanol-group in comparison to the control-group. Our findings support a tissue specificity for the toxic effects of ethanol towards the mitochondria and indicate that mitochondrial free radical mechanisms are involved in ethanol-induced toxicity in the brain.
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Química Encefálica , Etanol/toxicidad , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Radicales Libres , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Hepáticas/metabolismo , Consumo de Oxígeno , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismoRESUMEN
Cellular protection against free radical reactions was measured in myocardium from ethanol-fed rats using ethanol administration in drinking water as a model of moderate alcohol intoxication. The activities of Cu,Zn-superoxide dismutase (SOD) and glutathione-S-transferase were higher in ethanol-fed rats than in controls, whereas Mn-SOD, catalase and glutathione peroxidase activities were not altered by ethanol treatment. Myocardial zinc was higher and selenium concentration lower in ethanol-fed rats than in controls. Ethanol consumption, which failed to modify the myocardial vitamin E level, did not result in increased lipid peroxidation, but decreased cytosolic and membraneous protein thiols.
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Consumo de Bebidas Alcohólicas , Antioxidantes/metabolismo , Etanol/farmacología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Animales , Etanol/administración & dosificación , Radicales Libres , Masculino , Proteínas/análisis , Ratas , Ratas Sprague-Dawley , Fracciones Subcelulares/metabolismo , Compuestos de Sulfhidrilo/análisis , Superóxido Dismutasa/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisRESUMEN
Numerous experimental data reviewed in the present article indicate that free radical mechanisms contribute to ethanol-induced liver injury. Increased generation of oxygen- and ethanol-derived free radicals has been observed at the microsomal level, especially through the intervention of the ethanol-inducible cytochrome P450 isoform (CYP2E1). Furthermore, an ethanol-linked enhancement in free radical generation can occur through the cytosolic xanthine and/or aldehyde oxidases, as well as through the mitochondrial respiratory chain. Ethanol administration also elicits hepatic disturbances in the availability of non-safely-sequestered iron derivatives and in the antioxidant defense. The resulting oxidative stress leads, in some experimental conditions, to enhanced lipid peroxidation and can also affect other important cellular components, such as proteins or DNA. The reported production of a chemoattractant for human neutrophils may be of special importance in the pathogenesis of alcoholic hepatitis. Free radical mechanisms also appear to be implicated in the toxicity of ethanol on various extrahepatic tissues. Most of the experimental data available concern the gastric mucosa, the central nervous system, the heart, and the testes. Clinical studies have not yet demonstrated the role of free radical mechanisms in the pathogenesis of ethanol-induced cellular injury in alcoholics. However, many data support the involvement of such mechanisms and suggest that dietary and/or pharmacological agents able to prevent an ethanol-induced oxidative stress may reduce the incidence of ethanol toxicity in humans.
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Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Animales , Radicales Libres , Humanos , Hepatopatías Alcohólicas/etiologíaRESUMEN
A significant decrease in myocardial creatine kinase (CK) activity is apparent 2 hr after an acute ethanol load (2.3 g/kg, i.p.) in the rat. A lower dose (1.15 g/kg, i.p.), as well as ethanol addition in vitro up to 50 mM, do not affect this activity. Pretreatment with allopurinol (146 mumols/kg, i.p.) given at 16 hr and at 30 min before ethanol (2.3 g/kg) or with desferrioxamine (152 mumols/kg, i.p.) 30 min before ethanol failed to prevent the ethanol-induced decrease in CK activity. By contrast, propranolol (17 mumols/kg, i.p.), administered 30 min before ethanol elicited an enhanced CK activity in both control and ethanol-treated rats. This finding is likely related to the beta-blocking action and/or antioxidant properties of propranolol. Chronic ethanol intake (18% in calories) for 4 weeks also induced a decrease in myocardial CK activity, which could play a role in the pathogenesis of alcoholic cardiomyopathy.
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Consumo de Bebidas Alcohólicas/fisiopatología , Intoxicación Alcohólica/enzimología , Alopurinol/farmacología , Creatina Quinasa/metabolismo , Deferoxamina/farmacología , Miocardio/enzimología , Propranolol/farmacología , Animales , Relación Dosis-Respuesta a Droga , Etanol/farmacocinética , Masculino , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Ratas , Ratas EndogámicasRESUMEN
An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)
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Alcoholismo/fisiopatología , Etanol/farmacocinética , Peroxidación de Lípido/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Cardiomiopatía Alcohólica/fisiopatología , Radicales Libres , Humanos , Masculino , Ratas , Testículo/efectos de los fármacosRESUMEN
The kinetic scheme of the reaction of desferrioxamine (DFO) with O2-. was studied using pulse and gamma-radiolysis. The rate constant k(O2-. + DFO) is equal to 1.3 +/- 0.1 x 10(6) dm3 mol-1s-1 at pH 7.4. Studying the competition between DFO and ferricytochrome-c for O2-. generated by gamma-radiolysis, we observed that the nitroxide free radical resulting from the reaction of O2-. with DFO and the product(s) resulting from the decay of this nitroxide radical act inversely towards the cytochrome-c-Fe3+/cytochrome-c-Fe2+ redox couple. This explains the discrepancy between our value of k(O2-. + DFO) and the one measured previously using ferricytochrome-c for the detection of O2-. The reported results show that DFO acts as a powerful O2-. scavenger, and that the products resulting from the reaction of DFO with O2-. can initiate oxidative and/or reductive reactions that should be taken into account in interpreting the effects of DFO in vitro and in vivo.
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Deferoxamina , Superóxidos , Aniones , Radioisótopos de Cobalto , Deferoxamina/efectos de la radiación , Radicales Libres , Rayos gamma , Radiólisis de Impulso , Soluciones , AguaRESUMEN
Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.
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Intoxicación Alcohólica/metabolismo , Etanol/metabolismo , Hierro/metabolismo , Animales , Encéfalo/efectos de los fármacos , Catalasa/metabolismo , Deferoxamina/farmacología , Radicales Libres , Humanos , Hidróxidos , Radical Hidroxilo , Peróxidos Lipídicos/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimologíaRESUMEN
Two hours after an acute ethanol load (50 mmol/kg, i.p.), brain mitochondrial superoxide production was unchanged. This is contrary to our previous findings concerning liver mitochondria. On the other hand, the ethanol treatment caused a marked inhibition of respiration stimulated by phosphate plus ADP (with succinate or pyruvate plus malate as substrates) (state 3) in the brain mitochondria, whereas it did not exert any modification on the hepatic mitochondrial electron transport chain.