RESUMO
BACKGROUND: Graphistrength (©) C100 multiwalled carbon nanotubes (MWCNT) provide superior electrical and mechanical properties for various applications. The evaluation of the intrinsic hazard properties of Graphistrength(©) C100 is an essential step for safe use. A general feature of multiwalled carbon nanotubes after inhalation or intratracheal exposures is the induction of an inflammatory reaction in the lungs sometimes associated with local genotoxic effects. METHODS: After investigating different parameters for the aerosol generation and performing a 5-day inhalation range finding study, male and female Wistar rats were exposed nose-only for 90 days to target concentrations of 0.05, 0.25 and 5.0 mg/m(3) air of Graphistrength (©) C100 and sacrificed 24 h and 90 days after the last exposure. Broncho-alveolar lavage fluid (BALF) was also collected and analyzed for inflammatory parameters. Twenty-four hours post-exposure, chromosomal aberrations in the bone marrow cells were evaluated by the micronucleus test and DNA damages in the lung, kidney and liver cells by both the standard and the human 8-oxoguanine DNA N-glycosylase 1 (hOGG1)-modified comet assay. All studies were performed according to the OECD test guidelines. RESULTS: An inflammatory lung reaction and the release of inflammatory factors in the BALF were observed in all rats exposed to 5.0 mg/m(3), associated with changes in the differential white blood cells counts. The slight changes in BALF parameters at 0.25 mg/m(3) recovered and signs of lung clearance of the MWCNT were observed. No pathological changes were observed on the pleura. Neither increase in the number of micronucleated polychromatic erythrocytes nor increase in percent DNA damage were observed at any concentration. CONCLUSIONS: Lung inflammation characteristic of an overload with insoluble particles was observed after a 90-day exposure to 5.0 mg/m(3) of Graphistrength (©) C100. Clear signs of clearance and recovery were observed at 0.25 mg/m(3). No genotoxicity was detected locally in lung and distally in bone marrow, liver and kidney. Therefore, Graphistrength (©) C100 appears of low concern in term of local and systemic genotoxicity and a No-Observed Adverse Effect Concentration (NOAEC) of 0.25 mg/m(3) (0.28 mg/m(3) as actual concentration) was established for the repeated-dose toxicity.
Assuntos
Ensaio Cometa , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Nanotubos de Carbono/toxicidade , Pneumonia/induzido quimicamente , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Dano ao DNA , DNA Glicosilases/metabolismo , Relação Dose-Resposta a Droga , Feminino , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho da Partícula , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/patologia , Valor Preditivo dos Testes , Ratos Wistar , Medição de Risco , Fatores de TempoRESUMO
There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.
Assuntos
Acetaminofen/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Biológicos , Acetaminofen/metabolismo , Acetaminofen/urina , Animais , Meio Ambiente , Individualidade , Fígado/patologia , Espectroscopia de Ressonância Magnética , Masculino , Farmacogenética , Fenótipo , Ratos , Ratos Sprague-DawleyRESUMO
Amylase-resistant, periodic acid-Schiff (PAS)-positive inclusions were identified in the skeletal muscle of four of twenty-four purpose-bred beagle dogs from a routine toxicology study. Affected myofibers contained amorphous material filling up to 20% of the sarcoplasm that stained lightly basophilic with hematoxylin and eosin and was strongly PAS-positive with amylase resistance. Transmission electron micrographic examination of the inclusions revealed granular, non-membrane-bound, electron-dense material, consistent with polysaccharide. Although skeletal muscle inclusions with similar features have been reported in dogs in conjunction with systemic metabolic disorders and less often in muscle adjacent to nonmyogenic sarcomas, all four of these dogs lacked clinical or pathological findings diagnostic of a concurrent systemic metabolic or localized skeletal muscle disorder. Furthermore, these skeletal muscle inclusions were present in both vehicle- and test article-treated dogs and were considered an incidental finding that may occur spontaneously in clinically normal beagle dogs; as such, their presence in drug-treated animals should be interpreted with caution.
Assuntos
Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/veterinária , Polissacarídeos/metabolismo , Amilases/metabolismo , Animais , Cães , Feminino , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/ultraestrutura , Doenças Musculares/patologia , Reação do Ácido Periódico de Schiff , Polissacarídeos/ultraestrutura , Testes de ToxicidadeRESUMO
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Assuntos
Inibidores da Captação Adrenérgica/química , Norepinefrina , Piperazinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Incontinência Urinária por Estresse/tratamento farmacológico , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Cães , Humanos , Piperazinas/metabolismo , Piperazinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Phosphodiesterase 4 (PDE4) inhibitors are potential therapeutic agents but vascular injury and perivascular inflammation occurs frequently during preclinical toxicology testing of these drugs. The lesions induced by PDE4 inhibitors have been described mainly in rats but there is limited data available for monkeys and no data for dogs. Here we present the toxicological profile of CI-1044, a PDE4 inhibitor, administered orally to dogs. Dogs were treated for 4 days with 5, 10, 20 or 50 mg/kg of CI-1044, and a group of dogs was submitted to a 4-week recovery period after treatment with 20 mg/kg. CI-1044 induced disseminated vascular necrosis and inflammation in various organs/tissues from 20 mg/(kg day). The nasal turbinates and the scrotal skin were the most sensitive tissues but lesions were also observed in the stomach, heart, kidneys and, to a lower extent, in the liver, mesenteric lymph nodes, adrenals and lung. The inflammation was mainly characterized by an infiltration of polynuclear neutrophils, oedema and necrosis. The inflammation observed microscopically correlated with marked increases in serum amyloid A and C-reactive protein. Variations in these acute phase response proteins were detected 24 h after the first dose and were further increased over the course of the treatment. The vascular and inflammatory lesions were reversible over 4 weeks. In conclusion, the lesions induced by the PDE4 inhibitor CI-1044 in dogs differed from the haemodynamically mediated coronary arteritis reported with PDE3 inhibitors.
Assuntos
Reação de Fase Aguda/induzido quimicamente , Azepinas/toxicidade , Vasos Sanguíneos/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Niacinamida/análogos & derivados , Inibidores da Fosfodiesterase 4 , Reação de Fase Aguda/sangue , Reação de Fase Aguda/patologia , Administração Oral , Animais , Azepinas/sangue , Vasos Sanguíneos/patologia , Proteína C-Reativa/análise , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Feminino , Masculino , Necrose/induzido quimicamente , Necrose/patologia , Niacinamida/sangue , Niacinamida/toxicidade , Recuperação de Função Fisiológica , Proteína Amiloide A Sérica/análise , Testes de Toxicidade , Suspensão de TratamentoRESUMO
1 A novel animal model of spontaneous colonic inflammation, the multiple drug-resistant (mdr1) a(-/-) mouse, was identified by Panwala and colleagues in 1998. The aim of our study was to further characterise this model, specifically by measuring cytokines that have been implicated in inflammatory bowel disease (IBD) (IL-8 and IFN-gamma) in the colon/rectum of mdr1a(-/-) mice, and by determining the sensitivity of these, together with the macroscopic, microscopic and disease signs of colitis, to dexamethasone (0.05, 0.3 and 2 mg kg(-1) subcutaneously (s.c.) daily for 7 days). 2 All mdr1a(-/-) mice had microscopic evidence of inflammation in the caecum and colon/rectum, while control mice with the same genetic background did not. Significant increases in colon/rectum and caecal weights and also in cytokine levels (both IFN-gamma and IL-8) in homogenised colon/rectum were observed in mdr1a(-/-) mice compared to mdr1a(+/+) mice. 3 Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN-gamma or IL-8. 4 This study supports the similarity of the gastrointestinal inflammation present in mdr1a(-/-) mice to that of human IBD, in particular Crohn's disease. This has been demonstrated at the macroscopic and microscopic levels, and was supported further by elevations in colonic levels of IFN-gamma and IL-8 and the disease signs observed. The incidence of colitis was much higher than previously reported, with all mice having microscopic evidence of colitis. The limited variance between animals in the parameters measured suggests that this model is reproducible.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Colite/genética , Colite/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Citrobacter rodentium/isolamento & purificação , Colite/tratamento farmacológico , Colo/microbiologia , Citocinas/metabolismo , Dexametasona/uso terapêutico , Fezes/microbiologia , Helicobacter/isolamento & purificação , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Proteínas/metabolismo , Reto/patologiaRESUMO
Toxoplasmosis causes mortality in several avian species, especially passerine birds. Toxoplasmosis was diagnosed in a bar-shouldered dove (Geopelia humeralis) found dead at the zoo of Clères (France). The bird had necrotizing pneumonia and nephritis with intralesional tachyzoites of Toxoplasma gondii. The diagnosis was confirmed by immunostaining with polyclonal rabbit T. gondii antibodies and by transmission electron microscopy. To our knowledge, the bar-shouldered dove is a new host record for T. gondii.
Assuntos
Animais de Zoológico/parasitologia , Doenças das Aves/diagnóstico , Columbidae/parasitologia , Toxoplasma/isolamento & purificação , Toxoplasmose Animal/diagnóstico , Animais , Doenças das Aves/epidemiologia , Doenças das Aves/parasitologia , Diagnóstico Diferencial , França , Pulmão/parasitologia , Pulmão/patologia , Masculino , Pneumonia/diagnóstico , Pneumonia/parasitologia , Pneumonia/veterinária , Sarcocistose/diagnóstico , Sarcocistose/veterinária , Toxoplasma/ultraestrutura , Toxoplasmose Animal/epidemiologia , Toxoplasmose Animal/parasitologia , Vacúolos/parasitologiaRESUMO
We aimed to investigate the toxicity of carbon monoxide (CO) in rats with right ventricle (RV) remodeling induced by hypoxic pulmonary hypertension (PHT). A group of Wistar rats was exposed to 3-wk hypobaric hypoxia (H). A second group was exposed to 50 ppm CO for 1 wk (CO). A third group was exposed to chronic hypoxia including 50 ppm CO during the third week (H+CO). These groups were compared with controls. RV and left ventricle (LV) functions were assessed by echocardiography and transparietal catheterization. Ventricular perfusion was estimated with the fluorescent microsphere method. Results were confirmed by histology. PHT induced RV hypertrophy and function enhancement. In the H group, RV shortening fraction (RVSF; 71 +/- 12% vs. 41 +/- 2%) and RV end-systolic pressure (RVESP; 54 +/- 6 vs. 19 +/- 2 mmHg) were increased compared with controls. Moreover, myocardial perfusion was increased in the RV (36 +/- 2% vs. 22 +/- 2%) and decreased in the LV (64 +/- 3% vs. 78 +/- 2%). In the H+CO group, RVSF (45 +/- 3% vs. 71 +/- 12%) and RVESP (38 +/- 3 vs. 54 +/- 6 mmHg) were decreased compared with the H group. RV perfusion was decreased in the H+CO group compared with the H group (21 +/- 5% vs. 36 +/- 2%), and LV perfusion was increased (79 +/- 5% vs. 64 +/- 3%). PHT and RV hypertrophy were still present in the H+CO group, and fibroses localized in the RV were detected. Similar lesions were observed in an additional group exposed simultaneously to hypoxia and 50 ppm CO over 3 wk. We demonstrated that rats with established PHT were more sensitive to CO, which dramatically alters the RV adaptive response to PHT, leading to ischemic lesions.
Assuntos
Monóxido de Carbono/toxicidade , Hipertensão Pulmonar/complicações , Hipertrofia Ventricular Direita/etiologia , Hipóxia/complicações , Isquemia Miocárdica/induzido quimicamente , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Administração por Inalação , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Monóxido de Carbono/administração & dosagem , Carboxihemoglobina/metabolismo , Cateterismo Cardíaco , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hematócrito , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/sangue , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/sangue , Hipóxia/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/complicações , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacosRESUMO
A (1)H Nuclear Magnetic Resonance (NMR) spectroscopic investigation of the effects of single doses of four model hepatotoxins on male Sprague-Dawley rats showed that hypertyrosinemia was induced by three of the treatments (ethionine 300 mg/kg, galactosamine hydrochloride 800 mg/kg and isoniazid 400 mg/kg) but not by the fourth (thioacetamide 200 mg/kg). Concomitant histopathological and clinical chemistry analyses showed that hypertyrosinemia could occur with or without substantial hepatic damage and that substantial hepatic damage could occur without hypertyrosinemia. However, in the rats dosed with galactosamine hydrochloride, which showed highly variable amounts of liver damage at ca. 24 h after dosing, a clear relationship was found between the degree of hypertyrosinemia and the extent of the hepatic necrosis induced. In line with the cause of clinically observed Type II Tyrosinemia, we consider that the critical event in the onset of hepatotoxin-induced hypertyrosinemia is likely to be a reduction in hepatic tyrosine aminotransferase (TAT) activity. We discuss mechanisms by which TAT activity could be lost with special consideration given to pyridoxal 5'-phosphate (P5P) depletion and to the inhibition of protein synthesis. This analysis may have implications for the interpretation of clinical measures of liver status such as Fischer's ratio and the branched-chain tyrosine ratio (BTR).
Assuntos
Etionina/toxicidade , Galactosamina/toxicidade , Isoniazida/toxicidade , Fígado/efeitos dos fármacos , Tioacetamida/toxicidade , Tirosina/sangue , Animais , Proteínas Sanguíneas/análise , Fígado/patologia , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Tirosina Transaminase/metabolismoRESUMO
The time-related metabolic events in rat liver, plasma, and urine following hepatotoxic insult with allyl formate (75 mg/kg) were studied using a combination of high-resolution liquid state and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic methods together with pattern recognition analysis. The metabonomics results were compared with the results of conventional plasma chemistry and histopathological assessments of liver damage. Various degrees of liver damage were observed in different animals, and this variation was reflected in all of the analyses. Furthermore, each analysis revealed a high degree of functional and structural recovery by the end of the study. The allyl formate-induced changes included hepatocellular necrosis, hepatic lipidosis, decreased liver glycogen and glucose, decreased plasma lipids, increased plasma creatine and tyrosine, increased urinary taurine and creatine, and decreased urinary TCA cycle intermediates. The observed reductions in hepatic glycogen and glucose suggest increased glucose utilization and are consistent with the expected depletion of hepatic ATP following mitochondrial impairment, assuming that there is a consequent increase in energy production from glycolysis. The increase in plasma tyrosine is consistent with impaired protein synthesis, a known consequence of ATP depletion. Partial least squares-based cross-correlation of the variation in the liver and plasma NMR profiles indicated that the allyl formate-induced increase in liver lipids correlated with the decrease in plasma lipids. This suggests disruption in lipid transport from the liver to plasma, which could arise through impaired apolipoprotein synthesis, as with ethionine.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Ésteres do Ácido Fórmico/toxicidade , Hepatopatias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Análise Química do Sangue , Creatina/urina , Glucose/análise , Lipídeos/sangue , Fígado/patologia , Hepatopatias/patologia , Glicogênio Hepático/análise , Espectroscopia de Ressonância Magnética , Ratos , Taurina/urina , Tirosina/sangueRESUMO
Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin. Blood plasma samples taken at 24 h post-dosing and urine samples collected from 24-31 h post-dosing were analysed by (1)H NMR spectroscopy. Both hypercreatinaemia and hypercreatinuria were found in rats dosed with allyl formate (75 mg/kg), chlorpromazine (30 and 60 mg/kg), alpha-naphthylisothiocyanate (ANIT, 100 mg/kg) and thioacetamide (200 mg/kg), whilst significant hypercreatinuria, but not hypercreatinaemia, was found after dosing with thioacetamide (50 mg/kg). Neither hypercreatinaemia nor hypercreatinuria were found after dosing with allyl formate (25 mg/kg), ethionine (300 and 1000 mg/kg) or ANIT (30 mg/kg). Reduced feeding is known to cause hypercreatinuria in rats and, of the four hepatotoxins that induced hypercreatinaemia and hypercreatinuria at the given time-points, two, chlorpromazine and ANIT, also affected nutritional status with ketosis being clearly identifiable from the plasma (1)H NMR spectra. Thus, the creatine changes induced by ANIT and chlorpromazine are potentially attributable, in whole or in part, to reduced feeding rather than to liver effects alone and, consequently, the results were examined with and without inclusion of the ANIT and chlorpromazine data. With all of the data included, there were eight out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma alanine aminotransferase (ALT) activity. At the same time there were nine out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma aspartate aminotransferase (AST) activity. However, with the ANIT and chlorpromazine data excluded there was complete (six out of six points) correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma AST and ALT in the remaining data. Likewise, with all of the data included, there was some apparent correlation (correlation coefficient, r=0.80) between the group mean levels of plasma AST and plasma creatine when expressed relative to the mean values for controls sampled at the same time-point. However, with the ANIT and chlorpromazine data excluded, that correlation coefficient was increased to 0.95. The findings of these studies suggest that the ANIT- and chlorpromazine-induced creatine changes may have been caused by reduced feeding rather than by liver toxicity. The allyl formate and thioacetamide data indicate that hepatocellular necrosis is accompanied by increases in plasma and urinary creatine, and suggest the possibility of a quantitative relationship between the increases in plasma AST and the increases in plasma creatine that are associated with hepatocellular necrosis. The ethionine and ANIT data suggest that fatty liver (steatosis) and cholestatic damage may not be associated with hypercreatinaemia and hypercreatinuria.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/urina , Creatinina/sangue , Creatinina/urina , Distúrbios Nutricionais/metabolismo , Toxinas Biológicas/toxicidade , Administração Oral , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Espectroscopia de Ressonância Magnética , Masculino , Distúrbios Nutricionais/induzido quimicamente , Distúrbios Nutricionais/patologia , Ratos , Toxinas Biológicas/administração & dosagemRESUMO
As part of a wider metabonomic investigation into the early detection and discrimination of site-specific hepatotoxicity, male Sprague-Dawley rats were dosed with the model hepatotoxins allyl formate, ethionine and alpha-naphthylisothiocyanate (ANIT). Urine samples collected pre- and post-dose were examined by (1)H nuclear magnetic resonance (NMR) spectroscopy and the toxin-induced changes in urinary taurine and creatine excretion were quantified. Hypertaurinuria and hypercreatinuria were observed following allyl formate dosing, hypertaurinuria with no change in creatine excretion was observed after ethionine dosing, and hypotaurinuria and hypercreatinuria were observed after ANIT dosing. These changes are indicative of different effects on liver and it has been previously suggested that some hepatotoxin-induced changes in urinary taurine excretion may be due to altered hepatic cysteine utilisation. A related hypothesis is now presented that would explain the selective hypercreatinuria in terms of increased cysteine synthesis.
Assuntos
1-Naftilisotiocianato/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/urina , Creatinina/urina , Cisteína/biossíntese , Etionina/toxicidade , Ésteres do Ácido Fórmico/toxicidade , 1-Naftilisotiocianato/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Etionina/administração & dosagem , Ésteres do Ácido Fórmico/administração & dosagem , Injeções Intraperitoneais , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Taurina/urinaRESUMO
The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 +/- 2 mmHg in the C group, 35 +/- 2 mmHg in the CH group, and 14 +/- 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 +/- 1 vs. 34 +/- 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 +/- 0.40 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 +/- 0.08 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 +/- 4.2% vs. 36 +/- 2.8%) but decreased in the N-RE group [20 +/- 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 +/- 0.8 and 0.72 +/- 0.1 vs. 0.88 +/- 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia.