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Am J Physiol Heart Circ Physiol ; 294(6): H2627-36, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18408136

RESUMO

Studies have shown that p38 MAPK and nitric oxide (NO), generated by endothelial NO synthase (eNOS), play key roles under physiological and pathophysiological conditions. Although administration of 17beta-estradiol (E2) protects cardiovascular injury from trauma-hemorrhage, the mechanism by which E2 produces those effects remains unknown. Our objective was to determine whether the E2-mediated activation of myocardial p38 MAPK and subsequent eNOS expression/phosphorylation would protect the heart following trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent soft-tissue trauma (midline laparatomy) and hemorrhagic shock (mean blood pressure 35-40 mmHg for 90 min), followed by fluid resuscitation. Animals were pretreated with specific p38 MAPK inhibitor SB-203580 (SB; 2 mg/kg), and nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 30 mg/kg) 30 min before vehicle (cyclodextrin) or E2 (100 microg/kg) treatment, followed by resuscitation, and were killed 2 h thereafter. Cardiovascular performance and other parameters were measured. E2 administration following trauma-hemorrhage increased cardiac p38 MAPK activity, eNOS expression and phosphorylation at Ser(1177), and nitrate/nitrite levels in plasma and heart tissues; these were associated with normalized cardiac performance, which was reversed by SB administration. In addition, E2 also prevented trauma-hemorrhage-induced increase in cytokines (IL-6 and TNF-alpha), chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-1), and ICAM-1, which was reversed by l-NAME administration. Administration of E2 following trauma-hemorrhage attenuated cardiac tissue injury markers, myeloperoxidase activity, and nitrotyrosine level, which were reversed by treatment with SB and l-NAME. The salutary effects of E2 on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation.


Assuntos
Cardiotônicos/farmacologia , Estradiol/farmacologia , Cardiopatias/prevenção & controle , Proteína Quinase 11 Ativada por Mitógeno/metabolismo , Miocárdio/enzimologia , Choque Hemorrágico/tratamento farmacológico , Abdome/cirurgia , Animais , Calmodulina/metabolismo , Caveolina 1/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Cardiopatias/enzimologia , Cardiopatias/etiologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Imidazóis/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Masculino , Proteína Quinase 11 Ativada por Mitógeno/antagonistas & inibidores , Miocárdio/patologia , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III , Nitritos/metabolismo , Peroxidase/metabolismo , Fosforilação , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/complicações , Choque Hemorrágico/enzimologia , Choque Hemorrágico/patologia , Choque Hemorrágico/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulação para Cima , Função Ventricular/efeitos dos fármacos
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