RESUMO
BACKGROUND: Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation. METHODS: Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α). RESULTS: As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium. CONCLUSIONS: LED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.
Assuntos
Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/terapia , Neuroimunomodulação/fisiologia , Fototerapia/métodos , Fibrilação Ventricular/imunologia , Fibrilação Ventricular/terapia , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Neuroimunomodulação/efeitos da radiação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fibrilação Ventricular/metabolismoRESUMO
Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.
Assuntos
Cardiotônicos/uso terapêutico , Quimiocina CCL5/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Fator Plaquetário 4/metabolismo , Multimerização Proteica/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Quimiocina CCL5/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/imunologia , Peptídeos Cíclicos/farmacologia , Fator Plaquetário 4/imunologia , Multimerização Proteica/imunologia , Resultado do TratamentoRESUMO
Erigeron multiradiatus (Lindl.) Benth. has been used in Tibet folk medicine to treat various inflammatory diseases. The aim of this study was to investigate antimyocardial ischemia and reperfusion (I/R) injury effect of caffeoylquinic acids derivatives of E. multiradiatus (AE) in vivo and to explain underling mechanism. AE was prepared using the whole plant of E. multiradiatus and contents of 6 caffeoylquinic acids determined through HPLC analysis. Myocardial I/R was induced by left anterior descending coronary artery occlusion for 30 minutes followed by 24 hours of reperfusion in rats. AE administration (10, 20, and 40 mg/kg) inhibited I/R-induced injury as indicated by decreasing myocardial infarct size, reducing of CK and LDH activities, and preventing ST-segment depression in dose-dependent manner. AE decreased cardiac tissue levels of proinflammatory factors TNF-α and IL-6 and attenuated leukocytes infiltration. AE was further demonstrated to significantly inhibit I-κB degradation, nuclear translocation of p-65 and phosphorylation of JNK. Our results suggested that cardioprotective effect of AE could be due to suppressing myocardial inflammatory response and blocking NF-κB and JNK activation pathway. Thus, caffeoylquinic acids might be the active compounds in E. multiradiatus on myocardial ischemia and be a potential natural drug for treating myocardial I/R injury.
Assuntos
Erigeron/química , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/imunologia , Miocárdio/imunologia , Miocárdio/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Ácido Quínico/análogos & derivados , Animais , Masculino , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/cirurgia , Ácido Quínico/química , Ratos , Ratos Sprague-DawleyRESUMO
Icaritin (ICT) is a traditional Chinese medicinal herb proved to be neuroprotective and exerts promoting effects on cardiac differentiation. However, its role in cardioprotection against myocardial ischemia/reperfusion (MI/R) injury remains largely unknown. This study aimed to investigate the effects of ICT treatment on MI/R injury and the underlying mechanisms. Rats were subjected to 30 min of myocardial ischemic insult followed by 3 h of reperfusion. ICT (3, 10, and 30 mg/kg) was administered intraperitoneally 10 min before reperfusion. ICT treatment at the dose of 10 and 30 mg/kg improved cardiac function and limited infarct size following MI/R. Meanwhile, ICT reduced plasma creatine kinase (CK), lactate dehydrogenase (LDH) activities and cardiomyocyte apoptosis in I/R heart tissue. Moreover, ICT treatment not only inhibited the pro-inflammatory cytokine TNF-α production and increased the anti-inflammatory cytokine IL-10 level in myocardium but also reduced the increase in the generation of superoxide content and malondialdehyde (MDA) formation and simultaneously increased the anti-oxidant capability in I/R hearts. Furthermore, ICT treatment increased Akt phosphorylation and inhibited PTEN expression in I/R hearts. PI3K inhibitor wortmannin inhibited ICT-enhanced Akt phosphorylation, and blunted ICT-mediated anti-oxidative and anti-inflammatory effects and cardioprotection. Our study indicated for the first time that ICT reduces inflammation and oxidative stress and protects against MI/R injury in rats, which might be via a PI3K-Akt-dependent mechanism.
Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Flavonoides/administração & dosagem , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Isquemia Miocárdica/genética , Isquemia Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/imunologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: The current study was designed to test our hypothesis that atorvastatin could reduce infarct size in intact mice by activating eNOS, specifically the eNOS in bone marrow-derived cells. C57BL/6J mice (B6) and congenic eNOS knockout (KO) mice underwent 45 min LAD occlusion and 60 min reperfusion. Chimeric mice, created by bone marrow transplantation between B6 and eNOS KO mice, underwent 40 min LAD occlusion and 60 min reperfusion. Mice were treated either with vehicle or atorvastatin in 5% ethanol at a dose of 10 mg/kg IV 5 min before initiating reperfusion. Infarct size was evaluated by TTC and Phthalo blue staining. RESULTS: Atorvastatin treatment reduced infarct size in B6 mice by 19% (p<0.05). In eNOS KO vehicle-control mice, infarct size was comparable to that of B6 vehicle-control mice (pâ=âNS). Atorvastatin treatment had no effect on infarct size in eNOS KO mice (pâ=âNS). In chimeras, atorvastatin significantly reduced infarct size in B6/B6 (donor/recipient) mice and B6/KO mice (p<0.05), but not in KO/KO mice or KO/B6 mice (pâ=âNS). CONCLUSIONS: The results demonstrate that acute administration of atorvastatin significantly reduces myocardial ischemia/reperfusion injury in an eNOS-dependent manner, probably through the post-transcriptional activation of eNOS in bone marrow-derived cells.
Assuntos
Atorvastatina/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico Sintase Tipo III/genética , Animais , Atorvastatina/uso terapêutico , Células da Medula Óssea/enzimologia , Transplante de Medula Óssea , Cardiotônicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/imunologia , Infiltração de Neutrófilos , Óxido Nítrico Sintase Tipo III/metabolismoRESUMO
CONTEXT: Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells. OBJECTIVE: The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation. MATERIALS AND METHODS: Sprague-Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60 mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30 min followed by reperfusion for 3 h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot. RESULTS: MLB administration significantly (p < 0.05) reduced: (1) ST-segment elevation (0.23 mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64 ng/ml) and CK-MB (49.57 ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36 pg/ml), IL-1ß (93.35 pg/ml) and IL-6 (96.84 pg/ml) levels, (6) MPO activity (1.82 U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression. DISCUSSION AND CONCLUSION: Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation.
Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Biomarcadores/sangue , Creatina Quinase Forma MB/sangue , Citocinas/sangue , Modelos Animais de Doenças , Eletrocardiografia , Proteínas I-kappa B/metabolismo , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/sangue , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Peroxidase/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Troponina I/sangueRESUMO
Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2'-deoxyuridine, 5'-triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.
Assuntos
Depressão/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Lactobacillus/imunologia , Sistema Límbico/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Probióticos/uso terapêutico , Tonsila do Cerebelo/imunologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Animais , Apoptose , Comportamento Animal , Região CA1 Hipocampal/imunologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Citocinas/sangue , Giro Denteado/imunologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Depressão/etiologia , Lactobacillus/crescimento & desenvolvimento , Sistema Límbico/imunologia , Sistema Límbico/patologia , Masculino , Infarto do Miocárdio/psicologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
PURPOSE: Traditional medicine has been appropriately identified as the most productive soil for the cultivation and harvesting of modern medicines. Herein, we postulate that safranal, an active constituent of Crocus sativus, owing to its strong antioxidant and anti-apoptotic potential, could be a valuable molecule in alleviating myocardial ischemia-reperfusion (IR) injury. METHODS: To evaluate this hypothesis, safranal (0.1-0.5 mL/kg/day, i.p.) or saline were administered to rats for 14 days, and on 15th day, one-stage ligation of left anterior descending coronary artery for 45 min was performed, followed by 60 min reperfusion. RESULTS: We concluded that safranal not only significantly decreased infarct size, but also improved left ventricular functions and the overall hemodynamic status of the myocardium. Interestingly, safranal enhanced phosphorylation of Akt/GSK-3ß/eNOS and suppressed IKK-ß/NF-κB protein expressions in IR-challenged myocardium. Our findings also imply that safranal exhibits strong anti-apoptotic potential, as evidenced by upregulated Bcl-2 expression and downregulated Bax and caspase3 expression with decreased TUNEL positivity. Moreover, safranal dose-dependently normalized myocardial antioxidant and nitrotyrosine levels, cardiac injury markers (LDH and CK-MB), and decreased TNF-α level in IR-insulted myocardium. Histopathological and ultrastructural findings correlated with the functional and biochemical outcomes showing preserved myocardial architecture and decreased inflammatory cells and edema. CONCLUSIONS: Taken together, these results provide convincing evidence of safranal as an invaluable molecule in myocardial IR setting probably due to its fortified antioxidant and anti-apoptotic potential.
Assuntos
Antioxidantes/uso terapêutico , Cicloexenos/uso terapêutico , Quinase 3 da Glicogênio Sintase/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Terpenos/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Cicloexenos/administração & dosagem , Relação Dose-Resposta a Droga , Etnofarmacologia , Glicogênio Sintase Quinase 3 beta , Coração/efeitos dos fármacos , Índia , Injeções Intraperitoneais , Masculino , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Terpenos/administração & dosagemRESUMO
We investigated the efficacy of Ligusticum wallichi aqueous extract (LWE) for myocardial protection against ischemia-reperfusion injury. Rats were fed for five weeks with either a control diet (sham and ischemia reperfusion (IR) model control groups) or a diet mixed with 0.2%, 0.4% or 0.6% Ligusticum wallichi extract. At the end of the five week period, hearts were excised and subjected to global ischemia for 30 min followed by reperfusion for 2 h. The hearts were compared for indices of oxidative stress and immunity activities. Administration of Ligusticum wallichi extract significantly decreased serum TNF-α, IL-6, IL-8, NO, MIP-1α, CRP and myocardium MDA levels, and serum CK, LDH and AST activities, and increased myocardium Na(+)-K(+)-ATPase, Ca(2+)-Mg(2+)-ATPase, NOS, SOD, CAT, GSH-Px and TAOC activities. The results indicate that Ligusticum wallichii extract treatment can enhance myocardial antioxidant status and improve the immunity profile in ischemic-reperfusion rats.
Assuntos
Coração/efeitos dos fármacos , Ligusticum/química , Miocárdio/metabolismo , Extratos Vegetais/farmacologia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Ligusticum/metabolismo , Masculino , Malondialdeído/sangue , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Oxirredutases/sangue , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Água/químicaRESUMO
Wogonin is a flavonoid isolated from Scutellaria baicalensis Georgi, a traditional Chinese medicine, and it possesses antioxidant and anti-inflammatory effects. The aim of this study is to investigate the in vivo effect of wogonin on myocardial ischemia/reperfusion injury in an open-chest anesthetized rat model, which was induced by 45-minute left coronary artery occlusion and 2-hour reperfusion. Rats were treated with wogonin (5, 10, and 20 mg/kg, intraperitoneal) 40 minutes before ischemia or treatment with 10 mg/kg of wogonin 15 minutes after occlusion. Pretreatment with 10 mg/kg of wogonin significantly delayed the occurrence of ventricular premature contractions and tachycardia, and it suppressed the incidence of ventricular tachycardia and ventricular fibrillation, and mortality elicited by ischemia when compared with that in the control group, accompanied by reducing the arrhythmia scores. After 2-hour reperfusion, pretreatment and posttreatment with wogonin significantly reduced the infarct size and plasma levels of creatine kinase muscle-brain fraction and lactate dehydrogenase. Wogonin also significantly reduced the elevation of plasma tissue necrosis factor-α and superoxide anion production in the myocardium with ischemia/reperfusion. The expression of monocyte chemoattractant protein-1, phosphorylated p38 mitogen-activated protein kinase, p65 and IκBα, and active caspase-3 in ischemic myocardium pronouncedly increased in the control group; these were significantly attenuated by treatment with wogonin. In conclusion, wogonin demonstrated in vivo cardioprotective effects by the attenuation of the severity of ischemia-induced arrhythmias and irreversible ischemia/reperfusion injury, which is associated with its antioxidant capacity and anti-inflammatory effects. The suppression of nuclear factor-κB and p38 mitogen-activated protein kinase activation and the inhibition of monocyte chemoattractant protein-1 expression contribute to the beneficial effects of wogonin.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Arritmias Cardíacas/tratamento farmacológico , Flavanonas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/patologia , Western Blotting , Quimiocina CCL2/biossíntese , Quimiocina CCL2/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flavanonas/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , NF-kappa B/biossíntese , NF-kappa B/imunologia , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.
Assuntos
Antifibrinolíticos/farmacologia , Leucócitos/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Infiltração de Neutrófilos/efeitos dos fármacos , Ácido Aminocaproico/farmacologia , Animais , Aprotinina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/imunologia , Microvasos/patologia , Microvasos/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/reabilitação , Inibidores de Serina Proteinase/farmacologia , Ácido Tranexâmico/farmacologiaRESUMO
1. It has been shown that phloroglucinol has anti-inflammatory and anti-oxidant properties. Both inflammatory cell infiltration and myeloperoxidase (MPO) activation play an important role in myocardial reperfusion injury. The aim of the present study was to explore the effect of phloroglucinol on myocardial reperfusion injury and the mechanisms involved. 2. Anaesthetized rats were pretreated with phloroglucinol (15 or 30 mg/kg, i.g.) or vehicle (5 mmol/L carboxymethyl cellulose sodium) 30 min prior to experimentation. The left main coronary artery was subjected to 1 h occlusion followed by 3 h reperfusion. Infarct size, the release of creatine kinase (CK), inflammatory cell infiltration, MPO activity and protein content, catalase in the blood and myocardium, and myocardial apoptosis were measured. 3. Following myocardial ischaemia and reperfusion in vehicle-treated rats, infarct size was 43.5 ± 3.7% (relative to the area at risk). Accompanying detrimental changes included elevated CK, enhanced inflammatory cell infiltration, high numbers of myocardial apoptotic cells, elevated caspase 3 activity, increased MPO activity and content in the plasma and myocardium and reduced catalase activity. These effects were attenuated by pretreatment with both doses of phloroglucinol (15 and 30 mg/kg, i.g.). 4. The results of the present study suggest that phloroglucinol protects the myocardium against ischaemia-reperfusion injury in rats and that its beneficial effects are related to inhibition of MPO activity and inflammatory cell infiltration.
Assuntos
Traumatismo por Reperfusão Miocárdica/prevenção & controle , Infiltração de Neutrófilos/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Floroglucinol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cardiotônicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Inflamação/imunologia , Masculino , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Infiltração de Neutrófilos/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To evaluate the myocardial protective effect of Gualou Xiebai Banxia decoction GXBD) and explore the mechanisms of inhibition of NF-kappa B activation and blockade of inflammatory responses induced by ischemia-reperfusion in rats. METHODS: Twenty-four Sprague Dawley (SD) rats were randomly divided into three groups. Rats in the treatment group received GXBD (13 g crude drug/kg) for three weeks, while rats in the model control and normal control groups received equal volumes of distilled water. On the 22nd day, rats in the ischemia-reperfusion (I/R) control and GXBD-treated groups underwent 30 min occlusion of the left anterior descending (LAD) coronary artery, followed by 120 min reperfusion. Electrocardiogram was recorded, and the activities of cardiac enzymes, cytokines, and NF-kappaB were assessed after I/R. RESULTS: Compared with the I/R control group, GXBD treatment restored the activity of the specific myocardial-injury marker creatine kinase (CK) and lactate dehydrogenase (LDH), and inhibited the inflammatory response involving the nuclear factor-kappaB (NF-KB) pathway, including down-regulation of interleukin (IL)-1beta and IL-6, and up-regulation of IL-10 gene expression. CONCLUSION: GXBD strongly reduced myocardial impairment in our I/R model, including inhibition of NF-kappaB activation and inflammatory cytokine responses.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NF-kappa B/imunologia , Animais , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Traumatismo por Reperfusão Miocárdica/imunologia , NF-kappa B/genética , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To investigate the protective effects of Xuefu Zhuyu decoction on myocardium ischemia reperfusion injury in rats. METHOD: 36 SD rats were divided into 3 groups randomly, sham-operated group, model group, Xuefu Zhuyu decoction group. The model of MI/RI of the myocardium was reproduced by ligation of left descending artery for 30 min followed by releasing the ligation for 2 hours in rats. Serum contents of LDH-L, CK were measured, the levels of serum IL-1beta, IL-6 and IL-10 were measured and myocardial ultrastructure at the ischemia region was observed under the transmission electron microscope after myocardial reperfusion injury. RESULT: Compared with model group, IL-1beta, IL-6 and IL-10 levels were lower, myocardial ultrastructural changes were improved in Xuefu Zhuyu decoction group (P < 0.01), however, serum contents of LDH-L and CK no significant difference were found among the model group and Xuefu Zhuyu decoction group. CONCLUSION: Xuefu Zhuyu decoction can protect myocardium from MI/RI, the mechanism of action was related to inhibiting inflammatory reaction and reducing arrhythmia and the injury of the myocardial ultrastructure.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Interleucina-10/imunologia , Interleucina-6/imunologia , Masculino , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The shortage of pediatric heart donors often necessitates considerable travel time and, as a result, prolonged donor heart ischemia. This excessive hypothermic storage may contribute markedly to myocardial dysfunction in the recipient. METHODS: We investigated the role of leukocyte-endothelial interactions in this dysfunction in an isolated, immature (mean age, 11.8 +/- 1.6 days) swine heart model using a monoclonal antibody against a leukocyte adhesion molecule. We studied a total of 20 hearts subjected to 6 hours of cardioplegic arrest at 4 degrees C. Group M1/70 (n = 6) received at reperfusion 15 micrograms/mL of a monoclonal antibody F(ab')2 fragment to CD11b, the alpha-subunit of the leukocyte adhesion molecule Mac-1. Group MB10.6 (n = 8) received 15 micrograms/mL of the swine unreactive F(ab')2 MB10.6, and the third group received saline vehicle. RESULTS: Administration of M1/70 resulted in improved postischemic recovery of ventricular function compared with the two control groups (p < 0.05). CONCLUSIONS: These data implicate leukocyte-endothelial interactions mediated by the leukocyte adhesion molecule CD11b in myocardial dysfunction after long-term hypothermic ischemia. Specific antiadhesion strategies such as this may safely extend storage time for pediatric donor hearts.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Soluções Cardioplégicas/uso terapêutico , Criopreservação/métodos , Antígeno de Macrófago 1/imunologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Preservação de Órgãos/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Transplante de Coração , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Suínos , Fatores de Tempo , Função Ventricular/efeitos dos fármacosRESUMO
Using a thromboxane A2 receptor-specific antagonist, SQ 30,741, this study was undertaken to define the role of thromboxane A2 in postischemic myocardial reperfusion injury and in the heparin-protamine reaction. Eighteen heparinized (300 units/kg) sheep were placed on cardiopulmonary bypass (CPB) after complete instrumentation, cooled to 28 degrees C, and had their aortas crossclamped for 1 hour. They were then rewarmed to 36 degrees C and weaned from CPB without inotropic support. Control sheep (n = 6) received a saline infusion throughout the procedure. Bolus animals (n = 6) received 5 mg/kg of SQ 30,741 at 5 minutes after discontinuation of CPB and before protamine sulfate administration. Infusion animals (n = 6) received an SQ 30,741 bolus of 5 mg/kg followed by a continuous infusion of 5 mg.kg-1 hr-1 of SQ 30,741 initiated before CPB. All animals received 5 mg/kg of protamine sulfate over a 15-second period 15 minutes after being weaned from CPB. Control animals exhibited significantly decreased global myocardial function after the 1-hour ischemic interval. Further significant functional decline and increase in pulmonary pressure occurred after protamine sulfate administration. Bolus animals experienced a similar postischemic injury, but had no further decrease in function following protamine infusion. Infusion animals had significantly improved global myocardial function after bypass compared with both other groups and were also protected from the deleterious effects of protamine sulfate administration.(ABSTRACT TRUNCATED AT 250 WORDS)