RESUMO
PURPOSE: MTS is elicited during open abdominal surgery and is characterized by facial flushing, hypotension, and tachycardia in response to the release of prostacyclin (PGI2) to plasma. MTS seems to affect postoperative morbidity, but data from larger cohorts are lacking. We aimed to determine the impact of severe mesenteric traction syndrome (MTS) on postoperative morbidity in patients undergoing open upper gastrointestinal surgery. METHODS: The study was a secondary analysis of data from three cohorts (n = 137). The patients were graded for severity of MTS intraoperatively, and hemodynamic variables and blood samples for plasma 6-keto-PGF1α, a stable metabolite of PGI2, were obtained at defined time points. Postoperative morbidity was evaluated by the comprehensive complication index (CCI) and the Dindo-Clavien classification (DC). RESULTS: Patients undergoing either esophagectomy (n = 70), gastrectomy (n = 22), liver- (n = 23), or pancreatic resection (n = 22) were included. Severe MTS was significantly associated with increased postoperative morbidity, i.e., CCI ≥ 26.2 (OR 3.06 [95% CI 1.1-6.6]; p = 0.03) and risk of severe complications, i.e., DC ≥3b (OR 3.1 [95% CI 1.2-8.2]; p = 0.023). Furthermore, patients with severe MTS had increased length of stay (OR 10.1 [95% CI 1.9-54.3]; p = 0.007) and were more likely to be admitted to the intensive care unit (OR = 7.3 [95% CI 1.3-41.9]; p = 0.027), but there was no difference in 1-year mortality. CONCLUSION: Occurrence of severe MTS during upper gastrointestinal surgery is associated with increased postoperative morbidity as indicated by an increased rate of severe complications, length of stay, and admission to the ICU. It remains to be determined whether inhibition of MTS enhances postoperative recovery.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Mesentério/cirurgia , Idoso , Dinamarca/epidemiologia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Epoprostenol/sangue , Feminino , Rubor/sangue , Rubor/etiologia , Humanos , Hipotensão/sangue , Hipotensão/etiologia , Complicações Intraoperatórias/sangue , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/etiologia , Masculino , Pessoa de Meia-Idade , Morbidade , Síndrome , Taquicardia/sangue , Taquicardia/etiologiaRESUMO
The mesenteric traction syndrome (MTS) is associated with prostacyclin (PGI2) facilitated systemic vasodilatation during surgery and is identified by facial flushing. We hypothesized that severe facial flushing would be related to the highest concentrations of plasma PGI2 and accordingly to the highest levels of skin blood flow measured by laser speckle contrast imaging (LSCI). Patients scheduled for major upper abdominal surgery were consecutively included. Within the first hour of the procedure, facial flushing was scored according to a standardized scale, and skin blood flow (LSPU) was continuously measured on the forehead and the cheeks by LSCI. Arterial blood samples for 6-keto-PGF1α (stable metabolite of PGI2) and hemodynamic variables were obtained at defined time points. Overall, 66 patients were included. After 15 min of surgery, patients with severe flushing demonstrated the highest plasma 6-keto-PGF1α concentration and the most significant decrease in systemic vascular resistance. Accordingly, the skin blood flow on the forehead (238 [201-372] to 562 LSPU [433-729]) and the cheeks (341 [239-355] to 624 LSPU [468-917]) increased and were significantly higher than for patients with moderate or no flushing (both, P = 0.04). A cut-off value for skin blood flow could be defined for both the cheeks and the forehead for patients with severe flushing vs. no flushing (425/456 LSPU, sensitivity 75/76% and specificity 80/85%). MTS is linked to an increase in facial skin blood flow during upper gastrointestinal surgery. By applying LSCI, it is possible to quantitatively register facial blood flow, and thereby provide an objective tool for intraoperative verification of MTS.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Epoprostenol/sangue , Rubor , Neoplasias Gastrointestinais/cirurgia , Trato Gastrointestinal/cirurgia , 6-Cetoprostaglandina F1 alfa/metabolismo , Adolescente , Adulto , Idoso , Anestesia , Artérias/patologia , Face , Feminino , Neoplasias Gastrointestinais/complicações , Hemodinâmica , Humanos , Lasers , Fígado/cirurgia , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Pâncreas/cirurgia , Complicações Pós-Operatórias , Pele/irrigação sanguínea , Estômago/cirurgia , Síndrome , Resistência Vascular , Vasodilatação , Adulto JovemRESUMO
OBJECTIVE: This study aimed to investigate the protective effects of baicalin on myocardial infarction in rats and explore the related mechanisms. METHODS: Fifty Sprague Dawley rats were randomly divided into the control, model, and low-, medium- and high-dose baicalin groups. The latter 3 groups were intraperitoneally injected with baicalin, with a dose of 12.5, 25 and 50 mg/kg, respectively. Then, the myocardial infarction model was established. The hemodynamic of rats was tested, the serum lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), prostacyclin (PGI2) and thromboxane A2 (TXA2) were determined, the myocardial superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected, and the myocardial B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X (Bax) protein expressions were determined. RESULTS: Compared with the model group, in the high-dose baicalin group the ST segment height and LVEDP were significantly decreased (P<0.05), the LVSP was significantly increased (P<0.05), the serum LDH, CK-MB and TXA2 levels were significantly decreased (P<0.05), the PGI2 level was significantly increased (P<0.05), the myocardial SOD level was significantly increased (P<0.05), and the myocardial MDA level was significantly decreased (P<0.05); the myocardial Bcl-2 protein level was significantly increased, and the Bax protein level was significantly decreased (P<0.05). CONCLUSION: Baicalin has protective effects on myocardial infarction in rats. The possible mechanisms may be related to its resistance to oxidative stress, and up-regulation of Bcl-2 protein expression and down-regulation of Bax protein expression in myocardial tissue.
Assuntos
Flavonoides/farmacologia , Infarto do Miocárdio/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Creatina Quinase Forma MB/sangue , Ensaio de Imunoadsorção Enzimática , Epoprostenol/sangue , Genes bcl-2 , Hemodinâmica/efeitos dos fármacos , L-Lactato Desidrogenase/sangue , Malondialdeído/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Superóxido Dismutase/análise , Tromboxano A2/sangue , Resultado do Tratamento , Proteína X Associada a bcl-2/análiseRESUMO
Abstract Objective: This study aimed to investigate the protective effects of baicalin on myocardial infarction in rats and explore the related mechanisms. Methods: Fifty Sprague Dawley rats were randomly divided into the control, model, and low-, medium- and high-dose baicalin groups. The latter 3 groups were intraperitoneally injected with baicalin, with a dose of 12.5, 25 and 50 mg/kg, respectively. Then, the myocardial infarction model was established. The hemodynamic of rats was tested, the serum lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), prostacyclin (PGI2) and thromboxane A2 (TXA2) were determined, the myocardial superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected, and the myocardial B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X (Bax) protein expressions were determined. Results: Compared with the model group, in the high-dose baicalin group the ST segment height and LVEDP were significantly decreased (P<0.05), the LVSP was significantly increased (P<0.05), the serum LDH, CK-MB and TXA2 levels were significantly decreased (P<0.05), the PGI2 level was significantly increased (P<0.05), the myocardial SOD level was significantly increased (P<0.05), and the myocardial MDA level was significantly decreased (P<0.05); the myocardial Bcl-2 protein level was significantly increased, and the Bax protein level was significantly decreased (P<0.05). Conclusion: Baicalin has protective effects on myocardial infarction in rats. The possible mechanisms may be related to its resistance to oxidative stress, and up-regulation of Bcl-2 protein expression and down-regulation of Bax protein expression in myocardial tissue.
Assuntos
Animais , Flavonoides/farmacologia , Substâncias Protetoras/farmacologia , Infarto do Miocárdio/prevenção & controle , Valores de Referência , Superóxido Dismutase/análise , Tromboxano A2/sangue , Ensaio de Imunoadsorção Enzimática , Distribuição Aleatória , Reprodutibilidade dos Testes , Cromatografia Líquida de Alta Pressão , Epoprostenol/sangue , Resultado do Tratamento , Ratos Sprague-Dawley , Genes bcl-2 , Creatina Quinase Forma MB/sangue , Proteína X Associada a bcl-2/análise , Hemodinâmica/efeitos dos fármacos , L-Lactato Desidrogenase/sangue , Malondialdeído/análiseRESUMO
Abstract Purpose: To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices. Methods: A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline). Results: In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups. Conclusion: Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.
Assuntos
Animais , Masculino , Feminino , Coelhos , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/sangue , Tromboxano A2/sangue , Broncodilatadores/farmacologia , Epoprostenol/sangue , Endotelina-1/sangue , Troponina I/sangue , Óxido Nítrico/farmacologia , Embolia Pulmonar/patologia , Valores de Referência , Fatores de Tempo , Administração por Inalação , Ensaio de Imunoadsorção Enzimática , Distribuição Aleatória , Regulação para Baixo , Doença Aguda , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
RATIONALE: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. OBJECTIVE: To evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH. METHODS AND RESULTS: Male and female athymic rnu/rnu rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI2 (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI2 and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. CONCLUSIONS: In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.
Assuntos
Hipertensão Pulmonar/prevenção & controle , Fatores Sexuais , Linfócitos T Reguladores/fisiologia , Inibidores da Angiogênese/farmacologia , Animais , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Doença Crônica , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Sistema Enzimático do Citocromo P-450/análise , Sistema Enzimático do Citocromo P-450/metabolismo , Epoprostenol/antagonistas & inibidores , Epoprostenol/sangue , Epoprostenol/metabolismo , Feminino , Heme Oxigenase (Desciclizante)/análise , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Indóis/farmacologia , Oxirredutases Intramoleculares/análise , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Pulmão/metabolismo , Masculino , Prostaglandinas I/biossíntese , Pirróis/farmacologia , Ratos , Ratos Nus , Receptores de Estrogênio/análise , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Linfócitos T Reguladores/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
PURPOSE: The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia. METHODS: Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100ß, HIF-1α, IL-1ß, PGI2, TXA2, and GSH-Px. The levels or activities of these biomarkers in plasma were detected before and after ischemia. Concurrently, neurological deficit scores and cerebral infarct volumes were assessed. Based on a mathematic model, network balance maps and three integral disruption parameters (k, φ, and u) of the simplified crosstalk network were achieved. RESULTS: The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameter u values correlated significantly with neurological deficit scores and infarct volumes. CONCLUSION: Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia.
Assuntos
Isquemia Encefálica/sangue , Modelos Teóricos , Animais , Biomarcadores/sangue , Isquemia Encefálica/patologia , Epoprostenol/sangue , Glutationa Peroxidase/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Interleucina-1beta/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Tromboxano A2/sangueRESUMO
OBJECTIVES: The aim of this study was to investigate the role of prostacyclin (PGI2) in prolonged isolated thrombocytopenia (PT) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the effect of PGI2 on the activation and aggregation of platelets in PT. METHODS: We enrolled 37 patients with PT and 36 controls following allo-HSCT in this study. Platelet aggregation and activation and PGI2 levels were measured. Endothelial progenitor cells (EPCs) from either PT or control patients were cultured ex vivo with serum from either PT or control patients. PGI2 secretions were then measured. PGI2 was added to the platelets ex vivo, and platelet aggregation and activation and PI3K/Akt phosphorylation were analyzed. RESULTS: A higher PGI2 level was observed in the PT patients. The activation and aggregation of platelets were significantly lower in the PT patients. EPCs from PT patients cultured in PT serum secreted higher levels of PGI2, and PGI2 inhibited platelet activation and aggregation in a concentration-dependent manner ex vivo. PI3K/Akt phosphorylation of platelets was regulated by PGI2 after allo-HSCT. Disease status, serum PGI2 level and platelet aggregation were independent risk factors in patients with PT after allo-HSCT. CONCLUSIONS: Higher PGI2 levels and lower platelet activation and aggregation occurred simultaneously in PT patients. PGI2 inhibited platelet activation and aggregation, probably by regulating the phosphorylation of PI3K/Akt.
Assuntos
Epoprostenol/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Ativação Plaquetária , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trombocitopenia/sangue , Trombocitopenia/etiologia , Adulto , Plaquetas/metabolismo , Plaquetas/patologia , Epoprostenol/metabolismo , Feminino , Humanos , Masculino , Agregação Plaquetária , Transdução de Sinais/efeitos dos fármacos , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Transplante Homólogo , Adulto JovemRESUMO
OBJECTIVE: The purpose of the present study was to investigate the effects of the combination of aspirin, simvastatin in diabetic rat on platelet function. METHODS: Eight-week-old male Wistar rats were selected and randomly divided into diabetic group (n=48) and normal control group (n=48). Diabetic rats were injected with 1% STZ (65mg/kg, dissolved in 0.l mmol/L, pH 4.5 citrate buffer) to induce diabetic model and the rats in normal control group were injected with the same dose of citrate buffer. A rat with blood glucose greater than 16.8 mmol/L and along with diabetic symptoms of polydipsia, polyuria and weight loss was considered the successful model of diabetes. Diabetic rats and normal Wistar rats were randomly divided into 4 groups and given aspirin(10 mg/kg), simvastatin(2 mg/kg), combination of aspirin(10mg/kg) and simvastatin(2 mg/kg), PBS for 8 weeks, respectively. The platelet function and the expression of CD62P were evaluated. The levels of nitric oxide (NO), endothelin (ET), thromboxane B2(TXB2), prostacyclin (PGI2), adiponectin (APN), TXB2 were detected in the serum. The expressions of heme oxygenase-1(HO-1), HO-2, endothelial nitric oxide synthase(e-NOS), p-eNOS, B-cell lymphoma-2(Bcl-2), cyclooxygenase-2(COX-2) in thoracic aorta were evaluated by Western blot. RESULTS: Compared with control rats, diabetic rats had high platelet aggregation and activation (P<0.05), which treated aspirin also showed lower aspirin sensitivity (P<0.05). The combination of drugs upregulated the expression of HO-1, eNOS, p-eNOS, BCL-2, APN levels and decreased the expression of COX-2, and had a greater inhibitory effect on platelet aggregation and activation. The combination of drugs improved endothelial function, adjusted TXA2/PGI2 levels and increased NO levels, which resulted in a great potential antiplatelet effect. CONCLUSIONS: These results suggest that simvastatin may improvethe effect of aspirin on anti-platelet function in diabetic rats.
Assuntos
Aspirina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Epoprostenol/sangue , Masculino , Óxido Nítrico/sangue , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Wistar , Tromboxano B2/sangueRESUMO
Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl-ß-glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y12 antagonist cangrelor, while inhibition of thromboxane A2 formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I2 (PGI2) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI2 or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y12 receptors is important for efficient platelet lysosomal exocytosis by thrombin.
Assuntos
Difosfato de Adenosina/sangue , Plaquetas/metabolismo , Acetilglucosaminidase/sangue , Difosfato de Adenosina/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Plaquetas/efeitos dos fármacos , Epoprostenol/sangue , Exocitose/efeitos dos fármacos , Humanos , Proteínas de Membrana Lisossomal/biossíntese , Proteínas de Membrana Lisossomal/sangue , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptor PAR-1/sangue , Trombina/farmacologiaRESUMO
AIM: The primary objective of this study was to study the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) on pressure overload-induced cardiac remodeling in rats, as well as the endothelial mechanisms based on PGI2. METHODS: Six weeks following surgery, rats were divided randomly into the following groups: a sham group, a model group, an MHBFC 12 mg/kg/day group (MHBFC 12), an indomethacin 2 mg/kg/day group (Indo 2), and an Indo 2+ MHBFC 12 group. The MS 4000 organism signal system was used to record the rats' hemodynamic indices. Additionally, the heart weight was determined, and the cardiac remodeling index was calculated. HE and Masson's stains were utilized to perform histological analyses; the immunofluorescence was used to observe the microvessel density of myocardial tissue; the colorimetric method was used to determine the hydroxyproline content of cardiac tissue; the ELISA method was used to measure the plasma PGI2 content; and transmission electron microscopy was used to observe the ultrastructure of the myocardium. RESULTS: A hyperdynamic circulation state, cardiac remodeling, decreased microvessel density and decreased plasma PGI2 content were each observed in the model group compared with the sham group, in which any changes in the above parameters were effectively reversed by MHBFC. Single-use Indo administration resulted in the progression of these pathophysiological changes; however, MHBFC prevented the worsening of these parameters. CONCLUSION: MHBFC significantly reverses pressure overload-induced cardiac remodeling, and its mechanism may partially contribute to the amelioration of endothelial cell function and the augmentation of PGI2 synthesis and secretion.
Assuntos
Aorta Abdominal/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Chalconas/farmacologia , Constrição Patológica/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Constrição Patológica/sangue , Constrição Patológica/patologia , Constrição Patológica/cirurgia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/cirurgia , Epoprostenol/agonistas , Epoprostenol/sangue , Hemodinâmica/efeitos dos fármacos , Humanos , Hidroxiprolina/metabolismo , Indometacina/farmacologia , Ligadura , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Ratos , Ratos Sprague-DawleyRESUMO
Mesenteric traction syndrome (MTS) manifests in 58-87% of patients undergoing upper abdominal surgery and is characterised by a triad of hypotension, tachycardia, and flushing. Prostacyclin is released from the gut mucosa following intestinal eventration and cyclooxygenase antagonists prevent the development of MTS. Also the use of remifentanil appears to increase the incidence of MTS and hypotension is aggravated by epidural analgesia. Yet, prostacyclin may be important for maintaining microcirculation within the splanchnic area and preserve its mucosal barrier.
Assuntos
Rubor/fisiopatologia , Hipotensão/fisiopatologia , Taquicardia/fisiopatologia , Abdome/cirurgia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Epoprostenol/sangue , Rubor/tratamento farmacológico , Humanos , Hipotensão/tratamento farmacológico , Complicações Intraoperatórias/fisiopatologia , Circulação Esplâncnica/efeitos dos fármacos , Síndrome , Taquicardia/tratamento farmacológicoRESUMO
BACKGROUND: Prostacyclin has been shown to increase portal hypertension, but the mechanism is unclear. This study aimed to investigate whether the overproduction of prostacyclin (PGI2) in cirrhosis participates in the splanchnic vascular hyporesponsiveness to vasoconstrictors in cirrhotic rats. METHODS: Cirrhotic model was created by subcutaneous injection of 60% carbon tetrachloride (CCl4) corn oil solution combined with intermittent drinking of 5% alcohol, and age-matched rats served as controls. The isolated third-generation mesenteric arterioles were used to examine the contractile response to norepinephrine. The changes in vascular diameter were observed under a microscope imaging device. The plasma concentration of 6-ketone-prostaglandin F1alpha (6-keto-PGF1alpha, a stable metabolite of PGI2) was tested via enzyme immunoassays and the expression of cyclooxygenase (COX) in mesenteric arteries was detected by Western blotting. RESULTS: In parallel with the increase of plasma 6-keto-PGF1alpha, the contractile response of arterioles from cirrhotic rats to norepinephrine was significantly impaired compared with that from controls. Inhibition of PGI2 or protein kinase A with indomethacin or Rp-adenosine 3', 5'-cyclic monophosphothioate (Rp-cAMPS) partially reversed the vascular hypo-contractile response to norepinephrine in arterioles from cirrhotic rats. Indomethacin significantly decreased the plasma 6-keto-PGF1alpha. Furthermore, indomethacin significantly attenuated the effect of Rp-cAMPS on arterioles from cirrhotic rats. COX-1 expression was up-regulated in mesenteric arteries from cirrhotic rats, whereas COX-2 was not detectable in the mesenteric arteries from both cirrhotic and control rats. CONCLUSION: Enhanced COX-1 expression in cirrhotic rats resulted in elevated PGI2 production which partially contributed to the splanchnic vascular hyporesponsiveness to a vasoconstrictor via the protein kinase A pathway.
Assuntos
Epoprostenol/metabolismo , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Experimental/metabolismo , Circulação Esplâncnica , Vasoconstrição , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Tetracloreto de Carbono , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Epoprostenol/sangue , Etanol , Cirrose Hepática Alcoólica/etiologia , Cirrose Hepática Alcoólica/fisiopatologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/fisiopatologia , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais , Circulação Esplâncnica/efeitos dos fármacos , Regulação para Cima , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Puerarin, a main isoflavone glucoside derived from the Chinese medicine Radix puerariae, has been employed clinically to prevent and treat various cardiovascular disorders. However, little research has been performed to identify the in vivo effects of puerarin on the re-endothelialization and neointimal hyperplasia of injured vessels, and its detailed mechanisms of action remain to be elucidated. In this study, Sprague-Dawley rats were treated with puerarin at the dosages of 0, 50, and 100 mg·kg(-1)·day(-1) i.p. after balloon carotid denudation for 2 weeks. The results showed that puerarin accelerated re-endothelialization after surgery, resulting in a significant reduction of neointima formation. Moreover, puerarin increased the serum levels of vasodilators, such as nitric oxide and prostaglandin I(2), in a dose-dependent manner. In vitro, puerarin exhibited protective effects on late endothelial progenitor cells and mature endothelial cells, and inhibitory effects on the migration of vascular smooth muscle cells. Taken together, these data indicate that puerarin accelerates re-endothelialization, inhibits neointima formation, and attenuates vascular remodeling at sites of arterial injury, possibly due to the cytoprotective effects on endothelial lineage and the suppression of vascular smooth muscle cell migration.
Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Isoflavonas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Lesões das Artérias Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Epoprostenol/sangue , Isoflavonas/administração & dosagem , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Neointima/prevenção & controle , Óxido Nítrico/sangue , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Vasodilatadores/administração & dosagemRESUMO
Bradykinin B2 receptor-deleted mice (Bdkrb2(-/-)) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2(-/-) also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2(-/-) shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 µM to 15 ± 5 µM), and 6-keto-PGF1α (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2(-/-) platelets express increased NO, guanosine 3',5'-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2(-/-) platelets have reduced collagen-related peptide-induced integrin α2bß3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2(-/-) hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2(-/-), combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.
Assuntos
Angiotensina I/sangue , Plaquetas/metabolismo , Epoprostenol/sangue , Óxido Nítrico/sangue , Fragmentos de Peptídeos/sangue , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas/sangue , Receptores Acoplados a Proteínas G/sangue , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Transplante de Medula Óssea , AMP Cíclico/sangue , GMP Cíclico/sangue , Immunoblotting , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Fragmentos de Peptídeos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Receptor Tipo 2 de Angiotensina/sangue , Receptor B2 da Bradicinina/deficiência , Receptor B2 da Bradicinina/genética , Receptores Acoplados a Proteínas G/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Trombose/sangue , Fatores de TempoRESUMO
Minimally invasive surgery produced major changes in treating abdominal malignancies and early stage lung cancer. Laparoscopy and thoracoscopy are less traumatic than open surgery: allow faster recovery, shorter hospital stay, better cosmesis. Although these clinical benefits are important, prolonged disease-free interval, long-term survival with improved quality of life are most important endpoints for oncologic surgery. Major surgery causes significant alteration of immunological response, of particular importance in oncologic patients, as postoperative immunosuppression has been related to septic complications, lower survival rate, tumor spread and metastases. Clinical studies have shown laparoscopic surgery preserves better the patient's immunological function. Postoperative plasma peak concentrations of IL-6, IL-10, C-reactive protein (CRP) and TNF-alpha were lower after laparoscopic colonic resection. Prospective thoracoscopic VATS lobectomy trials found better preservation of lymphocyte T-cell function and quicker return of proliferative responses to normal, lower levels of CRP, thromboxane and prostacyclin. Immune function is influenced by the extent of surgical trauma. Minimally invasive surgery show reduced acute-phase responses compared with open procedures and better preservation of cellular immune mechanisms.
Assuntos
Biomarcadores/sangue , Laparoscopia , Neoplasias/imunologia , Neoplasias/cirurgia , Cirurgia Torácica Vídeoassistida , Neoplasias Abdominais/imunologia , Neoplasias Abdominais/cirurgia , Proteína C-Reativa/metabolismo , Colectomia/métodos , Intervalo Livre de Doença , Epoprostenol/sangue , Medicina Baseada em Evidências , Humanos , Hospedeiro Imunocomprometido , Interleucina-10/sangue , Interleucina-6/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Cuidados Pós-Operatórios , Linfócitos T/imunologia , Tromboxanos/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
PURPOSE: Mesenteric traction syndrome (MTS) is caused by PGI(2) release during abdominal procedures and is often observed during abdominal surgery. We have demonstrated that MTS occurs more frequently in cases using remifentanil than in those that are not. The aim of this study was to assess the prophylactic benefit of flurbiprofen axetil on MTS in patients undergoing abdominal surgery using remifentanil. METHODS: Thirty ASA physical status I and II patients were enrolled. They were scheduled to undergo abdominal surgery under general anesthesia with remifentanil and were randomly assigned to receive flurbiprofen axetil (group F) or saline (group C) preoperatively (n = 15 each). MTS was defined according to our simplified diagnostic criteria. Arterial blood pressure and heart rate were recorded, and the plasma 6-keto-PGF(1α) (a stable metabolite of PGI(2)) concentration was measured just before skin incision and at 20 and 60 min after skin incision (T(0), T(20), T(60)) to confirm the diagnosis of MTS. RESULTS: Twelve of 15 (80%) patients developed MTS in group C, whereas only 1 of 15 (6.7%) patients in group F developed MTS. At T(20), the group C patients showed significantly lower arterial blood pressure (P < 0.05) and a faster heart rate (P < 0.01) than those in group F. The mean plasma 6-keto-PGF(1α) concentration was significantly elevated in group C at T(20) (P < 0.01), whereas the plasma 6-keto-PGF(1α) level remained low throughout the observation period in group F. CONCLUSIONS: We found that preoperative administration of flurbiprofen axetil reduced the incidence of MTS during abdominal surgery with remifentanil analgesia.
Assuntos
Anestésicos Intravenosos/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Flurbiprofeno/análogos & derivados , Hipotensão/prevenção & controle , Laparotomia/efeitos adversos , Piperidinas/efeitos adversos , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/prevenção & controle , 6-Cetoprostaglandina F1 alfa/sangue , Abdome/cirurgia , Idoso , Anestesia Geral , Método Duplo-Cego , Epoprostenol/sangue , Feminino , Flurbiprofeno/uso terapêutico , Humanos , Hipnóticos e Sedativos , Infusões Intravenosas , Masculino , Midazolam , Pessoa de Meia-Idade , Medicação Pré-Anestésica , Estudos Prospectivos , Remifentanil , Circulação Esplâncnica/fisiologiaRESUMO
Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 µg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.
Assuntos
Pressão Sanguínea , Hipertensão/fisiopatologia , Receptor 4 Toll-Like/fisiologia , Vasoconstrição , Animais , Artérias/fisiopatologia , Ciclo-Oxigenase 1/sangue , Ciclo-Oxigenase 2/sangue , Epoprostenol/sangue , Regulação da Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Hipertensão/genética , Imunidade Inata , Interleucina-6/sangue , Masculino , Proteínas de Membrana/sangue , Artérias Mesentéricas/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Tromboxano A2/sangue , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: To explore the effects and mechanism of electroacupuncture combined with medium frequency therapy on lumbar nerve root compression. METHODS: Seventy-two Sprague-Dawley (SD) rats were randomly divided into a normal group, a sham operation group, a model group, an electroacupuncture group (EA group), a medium frequency group(MF group) and an electroacupuncture combined with medium frequency group (EA + MF group), twelve rats in each group. Models were established by surgery except the normal group and the sham operation group. Rats in the normal group, the sham operation group and the model group were not treated. In the EA group, the rats were treated by electroacupuncture at "Jiaji" (EX-B 2) and "Huantiao" (GB 30) etc., and by medium frequency at the "Jiaji" (EX-B 2) and "Huantiao"(GB 30) in the MF group. Rats in the EA + MF group were treated by both electroacupuncture and medium frequency. All treatments were started on the fifth day of established model, once a day for fourteen days. Rats' lower limb functions were observed before and after treatment, thromboxane B 2 (TXB 2) and prostacyclin F1alpha (PGF1alpha) in blood plasma were tested after treatment, and pathological changes in the local compressed nerve root were observed by light microscope. RESULTS: After treatment, the scores of rats' lower limb neurologic function in three therapy groups were significantly lower than before (all P < 0.01). Compared with the model group, TXB 2 in the EA group and the EA + MF group after treatment were decreased significantly (both P < 0.01), and PGF1alpha in the EA + MF group was increased significantly (P < 0.01), and TXB 2/PGF1alpha level were all regulated favorably in three therapy groups (all P < 0.01), and the pathological scores in the EA group and the EA + MF group were improved significantly (both P < 0.01). CONCLUSION: n Electroacupuncture combined with medium frequency has anti-inflammatory and analgesic effects in model rats with lumbar nerve root compression, and its mechanism may be related with the regulation of homeostasis M between TXB 2 and PGF1alpha so as to improve microcirculation.
Assuntos
Analgesia por Acupuntura , Estimulação Elétrica , Eletroacupuntura , Vértebras Lombares/imunologia , Radiculopatia/imunologia , Radiculopatia/terapia , Animais , Modelos Animais de Doenças , Estimulação Elétrica/instrumentação , Epoprostenol/sangue , Feminino , Humanos , Masculino , Radiculopatia/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tromboxano B2/sangueRESUMO
The antiplatelet and antithrombotic effects of ent-16ß,17-dihydroxy-kauran-19-oic acid (DDKA) isolated from Siegesbeckia pubescens were investigated with different methods both in vitro and in vivo. We tested the antithrombotic activity of DDKA in arterio-venous shunt model. The effects of DDKA on adenosine diphosphate (ADP)-, Thrombin-, Arachidonic acid-induced rat platelets aggregation were tested in vitro. We also assessed its bleeding side effect by measuring coagulation parameters after intravenous administration for 5 days and investigated the potential mechanisms underlying such activities. In vivo, DDKA significantly reduced thrombus weight in the model of arterio-venous shunt. Meanwhile, DDKA increased plasma cAMP level determined by radioimmunoassay in the same model. Notably, DDKA prolonged PT and APTT in rats after intravenous administration DDKA for successive 5 days. In vitro, pretreatment with DDKA on washed rat platelets significantly inhibited various agonists stimulated platelet aggregation and caused an increase in cAMP level in platelets activated by ADP. These findings support our hypothesis that DDKA possesses antiplatelet and antithrombotic activities. The mechanisms underlying such activities may involve the anticoagulatory effect and cAMP induction.