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1.
Ann Thorac Surg ; 86(2): 568-75, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18640335

RESUMO

BACKGROUND: Cardiac surgery can result in left ventricular ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative stress with release of myeloperoxidase. Although aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limit clinical utility. This study tested the hypothesis that different aprotinin doses cause divergent effects on left ventricular contractility, cytokine release, and oxidative stress in the context of I/R. METHODS: Left ventricular I/R (30 minutes I, 60 minutes R) was induced in mice, and left ventricular contractility (maximal end-systolic elastance) determined. Mice were randomly allocated to 2 x 10(4) kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 x 10(4) KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 x 10(4) KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively. RESULTS: After I/R, maximal end-systolic elastance fell by more than 40% from baseline (p < 0.05), and this effect was attenuated by 2 x 10(4) KIU/kg but not 4 x 10(4) KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 x 10(4) KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 x 10(4) KIU/kg aprotinin. CONCLUSIONS: Aprotinin influences left ventricular contractility, cytokine release, and oxidative stress, which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery.


Assuntos
Aprotinina/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Serina Proteinase/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Procedimentos Cirúrgicos Cardíacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Elasticidade , Processamento de Imagem Assistida por Computador , Interleucina-6/análise , Camundongos , Camundongos Endogâmicos , Miocárdio/enzimologia , Peroxidase/análise , Fator de Necrose Tumoral alfa/sangue , Função Ventricular Esquerda/fisiologia
2.
Am J Physiol Heart Circ Physiol ; 295(4): H1394-402, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18689500

RESUMO

The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein extracellular MMP inducer (EMMPRIN) causes increased MMP expression in vitro, and elevated levels occur in patients with LV failure. However, the direct consequences of a prolonged increase in the myocardial expression of EMMPRIN in vivo remained unexplored. Cardiac-restricted EMMPRIN expression (EMMPRINexp) was constructed in mice using the full-length human EMMPRIN gene ligated to the myosin heavy chain promoter, which yielded approximately a twofold increase in EMMPRIN compared with that of the age/strain-matched wild-type (WT) mice; EMMPRINexp (n=27) and WT (n=33) mice were examined at 3.2+/-0.1 or at 13.3+/-0.5 mo of age (n=43 and 26, respectively). LV end-diastolic volume (EDV) was similar in young EMMPRINexp and WT mice (54+/-2 vs. 57+/-3 microl), but LV ejection fraction (EF) was reduced (51+/-1 vs. 57+/-1%; P<0.05). In old EMMPRINexp mice, LV EDV was increased compared with WT mice values (76+/-3 vs. 58+/-3 microl; P<0.05) and LV EF was significantly reduced (45+/-1 vs. 57+/-2%; P<0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by >50% from WT values (P<0.05) and were accompanied by a twofold higher collagen content (P<0.05). Persistent myocardial EMMPRINexp in aging mice caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling. These findings suggest that EMMPRIN is an upstream signaling pathway that can play a mechanistic role in adverse remodeling within the myocardium.


Assuntos
Envelhecimento , Basigina/metabolismo , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Remodelação Ventricular , Fatores Etários , Animais , Basigina/genética , Colágeno/metabolismo , Ecocardiografia , Fibrose , Humanos , Imuno-Histoquímica , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Miocárdio/enzimologia , Miocárdio/patologia , Transdução de Sinais , Volume Sistólico , Regulação para Cima , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
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