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1.
Zhonghua Nei Ke Za Zhi ; 42(3): 153-6, 2003 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-12816694

RESUMO

OBJECTIVE: To investigate the signaling pathway involved in the insulin-elicited anti-apoptotic effect during myocardial ischemia and reperfusion (MI/R) in vivo. METHODS: Male Sprague-Dawley rats were anesthetized and subjected to 30 min of myocardial ischemia followed by 4h-reperfusion. Rats were randomly treated with intravenous infusion of saline (vehicle, 4 ml.kg(-1).h(-1)), insulin (60 U/L), or insulin + wortmannin 5 min before reperfusion and continuing throughout the 4h-reperfusion period. Cardiac myocyte apoptosis was determined both qualitatively and quantitatively by DNA laddering and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) methods. Myocardial nitric oxide (NO) was measured by using NO-specific chemiluminescence detector. Activations of Akt and p38 mitogen-activated protein kinase (MAPK) were determined by kinase activity assays using corresponding kinase activity assay kits (Cell Signaling). RESULTS: In the vehicle-treated rats, MI/R caused significant cardiac myocyte apoptotic death. Treatment with insulin produced a significant anti-apoptotic effect as evidenced by a marked reduction of apoptotic index [(8.0 +/- 2.9)% vs. (19.3 +/- 4.6)% of vehicle, P < 0.01] and decreased formation of myocardial DNA fragmentation. In addition, insulin treatment produced 2.7-fold increase (P < 0.01) of myocardial Akt activity and 28% increase of myocardial NO production (P < 0.05), while p38 MAPK activity changed insignificantly as compared with that of vehicle (P > 0.05). Both insulin-induced Akt activation and anti-apoptotic effect could be abrogated by wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor. CONCLUSION: In vivo treatment with insulin at the initial of reperfusion significantly reduced postischemic apoptotic death via the PI3-kinase-Akt signaling pathway. Akt, but not p38 MAPK, activation plays a key role in the insulin-induced anti-apoptotic effect in MI/R.


Assuntos
Apoptose/efeitos dos fármacos , Insulina/farmacologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Transdução de Sinais/efeitos dos fármacos , Animais , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno
2.
J Pharmacol Exp Ther ; 301(2): 543-50, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11961055

RESUMO

The present experiment determined the effects of glutathione and ascorbic acid, the two most important hydrophilic antioxidants, on myocardial ischemia-reperfusion injury and evaluated their relative therapeutic values. Isolated rat hearts were subjected to ischemia (30 min) and reperfusion (120 min) and treated with ascorbic acid, glutathione monoethyl ester (GSHme), or their combination at the onset of reperfusion. Administration of 1 mM GSHme alone, but not 1 mM ascorbic acid alone, significantly attenuated postischemic injury (P < 0.05 versus vehicle). Most interestingly, coadministration of ascorbic acid with GSHme markedly enhanced the protective effects of GSHme (P < 0.01 versus vehicle). The protection exerted by the combination of GSHme and ascorbic acid at 1 mM each was significantly greater than that observed with 1 mM GSHme alone (P < 0.05). Moreover, treatment with GSHme alone or GSHme plus ascorbic acid markedly reduced myocardial nitrotyrosine levels, suggesting that these treatments attenuated myocardial peroxynitrite formation. These results demonstrated that 1) GSHme, but not ascorbic acid, exerted protective effects against ischemia-reperfusion injury; and 2) the protective effects of GSHme were further enhanced by coadministration with ascorbic acid, suggesting a synergistic effect between GSHme and ascorbic acid.


Assuntos
Ácido Ascórbico/uso terapêutico , Glutationa/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Tirosina/análogos & derivados , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glutationa/metabolismo , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Incidência , Peroxidação de Lipídeos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo , Taquicardia/epidemiologia , Taquicardia/etiologia , Tirosina/metabolismo , Fibrilação Ventricular/epidemiologia , Fibrilação Ventricular/etiologia
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