RESUMO
We studied the effects of a new glutamic acid derivative, glufimet, on oxidative stress, activity of antioxidant enzymes, mitochondrial respiration, endothelial vasodilation and anti-platelet activity in female rats after exposure to 24-hour immobilization pain stress and 7-nitroindazole, a neuronal nitric oxide synthase (nNOS) inhibitor. A single dose administration of glufimet (29 mg/kg intraperitoneally) 10 minutes before stress exposure caused a decrease of NO metabolites in serum (by 27.2%) and heart homogenate (33.5% (p£0.05), respectively, compared with the control group. Administration of 7-nitroindazole with glufimet also decreased the studied parameters by 14.3% in the heart homogenate and by 30,3% in the brain (p£0.05) compared with stress exposed rats receiving only the nNOS inhibitor. Glufimet decreased the levels of primary and secondary products of lipid peroxidation (LPO), conjugated dienes by 20% (p£0.05) and 17.3% (p£0.05), ketodienes by 16% and 13.7%, malondialdehyde by 15% (p£0.05) and 26.6% (p£0.05) in the heart and brain mitochondria of stress exposed rats, respectively, compared with the control group. Glufimet administration also increased SOD activity (by 14.4% and 13.1%, respectively), catalase (by 19% and 26.8%, respectively) and glutathione peroxidase (GPx) activity (by 45.5% (p£0.05) and 7.3%, respectively). The antioxidant effect of glufimet may be also attributed to increased coupling between the processes of mitochondria respiration and oxidative phosphorylation. This was evidenced by an increase in the respiratory control ratio (RCR) (by 46.0% (p£0.05) for malate/glutamate and by 49,7% (p£0.05) for succinate) in the heart mitochondria. A statistically significant increase in RCR (by 37.3% (p£0.05)) was observed in stress exposed female rat brain mitochondria for succinate. RCRs differed significantly for succinate in the heart and brain of rats receiving glufimet after nNOS blockade. RCR increased by 62.3% (p£0.05) in the heart mitochondria and by 72.2% (p£0.05) in the brain mitochondria compared with the RCRs in stress exposed rats receiving 7-nitroindazole.
Assuntos
Antioxidantes/farmacologia , Ácido Glutâmico/farmacologia , Indazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Animais não Endogâmicos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Sinergismo Farmacológico , Feminino , Ácido Glutâmico/análogos & derivados , Glutationa Peroxidase/metabolismo , Coração/efeitos dos fármacos , Imobilização , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologiaRESUMO
Changes in the metabolism of female rats hanging by cervical dorsal skin fold within 24 hours were examined. It was found that stress exposure results in an increase of the concentration of the final nitric oxide metabolites in the blood serum and homogenates of the heart and brain of animals, intensification of processes peroxidation lipids and mitochondrial dysfunction in these organs. Thus increase of mean arterial blood pressure by 18.9 % from baseline and violation of platelet and plasma components of hemostasis. Inhibitor of neuronal NO-synthase 7-nitroindazole in the dose of 50 mg/kg aggravates of the studied parameters changes. Administration of an animal selective inhibitor of inducible NOS aminoguanidine (50 mg / kg) contributes to limiting the damaging effects of stress reaction.