RESUMO
Poly(ADP-ribose) polymerase (PARP), an enzyme that is important to the regulation of nuclear function, is activated by DNA strand breakage. In massive DNA damage, PARP is overactivated, exhausting nicotinamide adenine dinucleotide and leading to cell death. Recent studies have succeeded in reducing cellular damage in ischemia/reperfusion by inhibiting PARP. However, PARP plays an important part in the DNA repair system, and its inhibition may be hazardous in certain situations. We compared the short-time inhibition of PARP against continuous inhibition during ischemia/reperfusion using isolated rat hearts. The hearts were reperfused after 21 minutes of ischemia with a bolus injection of 3-aminobenzamide (3-AB) (10 mg/kg) followed by continuous 3-AB infusion (50 µM) for the whole reperfusion period or for the first 6 minutes or without 3-AB. At the end of reperfusion, contractile function, high-energy phosphate content, nicotinamide adenine dinucleotide content, and infarcted area were significantly preserved in the 3-AB 6-minute group. In the 3-AB continuous group, these advantages were not apparent. At the end of reperfusion, PARP cleavage had significantly proceeded in the 3-AB continuous group, indicating initiation of the apoptotic cascade. Thus, continuous PARP inhibition by 3-AB does not reduce reperfusion injury in the isolated rat heart, which may be because of acceleration of apoptosis.
Assuntos
Benzamidas/uso terapêutico , Cardiotônicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Infarto do Miocárdio/patologia , Miocárdio/enzimologia , NAD/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfocreatina/metabolismo , Fósforo/metabolismo , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Radioisótopos de Sódio , Falha de Tratamento , Função Ventricular Esquerda/fisiologiaRESUMO
Hemoglobin vesicle (HbV) could be a useful blood substitute in emergency medicine. The aim of this study was to clarify the effects of HbV on cardiac function after ischemia-reperfusion (I/R) ex vivo. Isolated rat hearts were perfused according to the Langendorff method. An ischemia-reperfusion group (n = 6) was subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. HbV (hemoglobin, 0.33 g/dL) was perfused before ischemia-reperfusion for 10 minutes (HbV group, n = 6). Hemodynamics were monitored, and tissue glutathione contents were measured. The redox state of reactive thiols in cardiac tissues was assessed by the biotinylated iodoacetamide labeling method. Left ventricular developed pressure was significantly recovered in the HbV group after 30 minutes of reperfusion (56.3 ± 2.8 mm Hg vs. ischemia-reperfusion group 27.0 ± 8.0 mm Hg, P < 0.05). Hemodynamic changes induced by HbV were similar to those observed when N-nitro-L-arginine methyl ester was perfused for 10 minutes before ischemia-reperfusion (L-NAME group). The oxidized glutathione contents of cardiac tissues significantly decreased, and biotinylated iodoacetamide labeling of thiols was maintained in both the HbV and the L-NAME groups. HbV improved the recovery of cardiac function after ischemia-reperfusion in isolated rat hearts. This mechanism is dependent on functional protection against thiol oxidation.
Assuntos
Substitutos Sanguíneos/uso terapêutico , Coração/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Lipossomas Unilamelares , Animais , Substitutos Sanguíneos/farmacologia , Catalase/metabolismo , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Ácido Láctico/metabolismo , Masculino , Miocárdio/enzimologia , Miocárdio/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , NG-Nitroarginina Metil Éster/uso terapêutico , Oxirredução/efeitos dos fármacos , Perfusão , Proteínas/metabolismo , Ácido Pirúvico/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controleRESUMO
The purpose of this study was to clarify the characteristics of improved ischemic tolerance induced by severe, short-term food restriction in isolated, perfused rat hearts. Male Wistar (8 week-old) rats were given a food intake equivalent to a 70% reduction on the food intake of ad-libitum fed rats for 11 days (FR group and AL group, respectively). After this period, hearts were isolated and perfused in the Langendorff mode, and subjected to 20 min of global ischemia followed by 30 min of reperfusion. Although the coronary flow rate in the FR group (63.0 +/- 3.1 ml/min/g dry weight) was higher than that in the AL group (47.1 +/- 1.3 ml/min/g dry weight) during preischemic perfusion, the lactate release into the coronary effluent and absolute values of +dP/dt and -dP/dt in the FR group (2422 +/- 161 and -1282 +/- 51) were inversely lower than in the AL group (2971 +/- 156 and -1538 +/- 74, respectively). An increase in ischemic contracture was suppressed in the FR group. Following reperfusion, cardiac function, high-energy phosphate content, and intracellular pH, as measured by 31P-nuclear magnetic resonance spectroscopy, had recovered to a much greater degree in the FR group than in the AL group. The serum T3 level was significantly lower in the FR group (2.7 +/- 0.1 pg/ml) than in the AL group (3.6 +/- 0.1 pg/ml), and the levels of triglycerides, free fatty acids, insulin, and glucose were also significantly lower in the FR group than in the AL group. The protein expressions of myocyte enhancer factor 2A, Na(+), K(+)-ATPase, and phospholamban in the cardiac tissue were higher in the FR group than in the AL group. These results suggested that severe, short-term food restriction improves ischemic tolerance in rat hearts via altered expression of functional proteins induced by low serum T3 levels, decreased coronary conductance, and change in metabolic flux.
Assuntos
Restrição Calórica , Metabolismo Energético , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Função Ventricular Esquerda , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Concentração de Íons de Hidrogênio , Insulina/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , Perfusão , Ratos , Ratos Wistar , Fatores de Tempo , Triglicerídeos/metabolismo , Tri-Iodotironina/metabolismo , Pressão VentricularRESUMO
BACKGROUND AND AIM: Although rabeprazole (RPZ), a proton pump inhibitor, has been reported to have a bactericidal effect on Helicobacter pylori (H. pylori), no studies have been conducted regarding the effect of RPZ on gastric mucosal lesion formation caused by this bacterium. In the present study, we investigated the effect of RPZ on H. pylori-associated gastric mucosal lesion formation. METHODS: Sixty-two male Mongolian gerbils were inoculated with H. pylori (ATCC43504) (Hp group) and 60 gerbils with the culture media alone (control group). Some gerbils in the Hp group and in the control group were injected with RPZ (1 mg/kg/day, for 7 days) at the 5th week. Gerbils were evaluated at the 12th, 24th and 48th weeks. RESULTS: In the Hp group, all gerbils were persistently infected for 24 weeks, but 36% became negative for H. pylori at the 48th week. In the Hp + RPZ group, 18% of gerbils at the 12th week, 40% at the 24th week, and 80% at the 48th week, became negative for H. pylori. The level of neutrophil infiltration was significantly decreased in the Hp + RPZ group in comparison to the Hp group, possibly through the effects of RPZ on initial bacterial colonization and resultant inflammation. Even in the gerbils that became H. pylori-negative, the level of neutrophil infiltration was lower in the Hp + RPZ group than in the Hp group. RPZ treatment significantly increased the level of the reduced form of glutathione (GSH) at the 48th week. The elevated levels of the reduced form of GSH may have been reduced by an antioxidation process in the H. pylori-positive Hp + RPZ group. CONCLUSION: Administration of RPZ not only inhibited gastric H. pylori colonization, but also reduced gastric mucosal inflammation in gerbils, possibly through its antibacterial action as well as pharmacological recruitment of the reduced form of GSH.