RESUMEN
Treprostinil (Remodulin®) is a Food and Drug Administration (FDA) approved prostacyclin analog to treat pulmonary arterial hypertension. Recently, treprostinil has been investigated to reduce ischemia-reperfusion injury (IRI) during transplantation, which currently has no approved treatment. A validated analytical method is necessary to measure treprostinil concentrations in biological specimens. Here, a novel, sensitive, and specific method to measure treprostinil concentrations in rat serum, human serum, and human plasma has been developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Biological samples were processed by protein precipitation before chromatography and 6-keto Prostaglandin F1α-d4 was used as an internal standard. A gradient method was established with a total run time of 4 min. The assay was linear over the range of 0.25-75.0 ng/ml with accuracy (92.97-107.87 %), intra-assay precision (1.16-3.34 %), and inter-assay precision (1.11-4.58 %) in all biological matrices, which are within FDA acceptance criteria. No significant variation in treprostinil or 6-keto Prostaglandin F1α-d4 concentrations were observed under the investigated storage conditions. This novel, sensitive, and specific LC/MS-MS method is cost-effective and suitable for measuring treprostinil concentrations in animal studies and human biological samples for clinical applications.
Asunto(s)
Epoprostenol , Daño por Reperfusión , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Humanos , Animales , Epoprostenol/análogos & derivados , Epoprostenol/sangre , Ratas , Cromatografía Liquida/métodos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/sangre , Masculino , Ratas Sprague-DawleyRESUMEN
Objective: To analyze and predict the progress of patients with lacunar infarction by analyzing the levels of serum NO, PGI2, and Ox-LDL produced by endothelial cells. Methods: 138 patients with lacunar infarction and 34 healthy people were selected. The selected samples were divided into progressive group, nonprogressive group, and control group for biochemical test and endothelial function test. The levels of serum NO, PGI2, and Ox-LDL were obtained. The observation indexes of different groups were compared for statistical analysis and multivariate logistic regression analysis. Results: The indexes of LI patients in the nonprogression group were different from those in the control group. The content of Ox-LDL in the nonprogression group was higher than that in the control group, while the indexes of serum NO and PGI2 were lower than that in the control group. The level of Ox-LDL in LI patients in the progressive group was much higher than that in healthy people in the control group seven days after admission, while the levels of serum NO and PGI2 were lower, and the difference of serum on was more obvious. The level of Ox-LDL in the progressive group was much higher than that in the nonprogressive group, while the levels of serum NO and PGI2 in the progressive group were lower, and the level of serum NO was significantly different from that in the nonprogressive group. Ox - LDL > 76.48 U/L, NO > 55.24 ummol/L, and PGI2 > 29.78 ng/L were independent risk factors for the progression of lacunar infarction. Conclusion: Because the patients with lacunar infarction have endothelium-dependent relaxation disorder, the changes of serum NO, PGI2, and Ox-LDL can be used as the evaluation index of the disease progress of patients with lacunar infarction and can be widely used in clinical detection.
Asunto(s)
Accidente Vascular Cerebral Lacunar , Infarto Cerebral , Progresión de la Enfermedad , Células Endoteliales , Epoprostenol/sangre , Humanos , Lipoproteínas LDL , Óxido Nítrico/sangreRESUMEN
BACKGROUND: Our previous study demonstrated the types of platelet dysfunction varied at early stage (â¼3âh) in trauma-induced coagulopathy (TIC) caused by different types of injuries. And arachidonic acid (AA)-dependent pathway inhibition in platelet seemed to be specific for TIC caused by multiple injury (MI). The aim of this research was to further study AA-dependent pathway inhibition in platelets in a rat model of TIC caused by MI and to explore its potential mechanisms. METHODS: Sprague-Dawley rat model of TIC caused by MI was established. We used thrombelastography with platelet mapping as a measure of platelet function to assess the inhibitory extent of AA-dependent activation pathway. Flow cytometry was used to determine the expression of activation-dependent granular protein P-selectin (CD62P). In addition, the plasma levels of 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1α), Prostaglandin E2, and Thromboxane B2 were assessed by enzyme-linked immuno sorbent assay. RESULTS: The inhibition rate of AA-dependent pathway after injury was significantly higher than that of control. The maximum amplitude decreased in the MI group, compared with that of control. The percentage of CD62P expression in the MI group was remarkably lower than that of control after AA treatment. The plasma concentrations of 6-Keto-PGF1α and PGE2 increased in the MI group. CONCLUSION: Platelets inhibition was observed in TIC caused by MI at early stage after injury, which might be partially attributed to AA-dependent activation pathway dysfunction. The increase of plasma Prostacyclin and PGE2 levels may contribute to the inhibition process.
Asunto(s)
Ácido Araquidónico/metabolismo , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/etiología , Traumatismo Múltiple/sangre , Traumatismo Múltiple/complicaciones , Activación Plaquetaria/fisiología , 6-Cetoprostaglandina F1 alfa/sangre , Animales , Plaquetas , Dinoprostona/sangre , Modelos Animales de Enfermedad , Epoprostenol/sangre , Masculino , Selectina-P/sangre , Pruebas de Función Plaquetaria , Ratas , Ratas Sprague-Dawley , Tromboelastografía , Tromboxano B2/sangreRESUMEN
PURPOSE: We examined whether 2 wk of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function. METHODS: Study participants were healthy young men (n = 12; 20-24 yr of age). Leg microvascular function was determined before the intervention, after the immobilization period, and after a 4-wk exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine and sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as prooxidant and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples: endothelial nitric oxide synthase, NADPH oxidase (NOX p67 and NOX gp91), and superoxide dismutase 2 (SOD2). RESULTS: The acetylcholine-induced change in vascular conductance was reduced after the 2 wk of immobilization (P = 0.003), tended to increase (P = 0.061), and was back to baseline levels after the subsequent 4 wk of exercise training. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P = 0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of endothelial nitric oxide synthase in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P = 0.002). NOX p67, NOX gp91, and SOD2 in the experimental leg remained unaltered with immobilization, and SOD2 was higher than preimmobilization after 4 wk of training (P < 0.001). CONCLUSIONS: The study shows that 2 wk of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that 4 wk of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.
Asunto(s)
Endotelio Vascular/fisiología , Inmovilización/efectos adversos , Pierna/irrigación sanguínea , Microcirculación/fisiología , Músculo Liso Vascular/fisiología , Acondicionamiento Físico Humano/fisiología , 6-Cetoprostaglandina F1 alfa/sangre , Epoprostenol/sangre , Humanos , Masculino , Proteínas Musculares/metabolismo , Norepinefrina/sangre , Flujo Sanguíneo Regional , Factores de Tiempo , Vasoconstricción/fisiología , Vasodilatación/fisiología , Adulto JovenRESUMEN
As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil (TRE) in children with pulmonary arterial hypertension. The trial consisted of the following 3 cohorts: transition from parenteral (cohort 1) or inhaled (cohort 2) TRE, or de novo addition (cohort 3). Oral TRE was dosed 3 times daily. PK samples were obtained before an oral TRE dose, and at 2, 4, 6, and 8 hours thereafter. The PK parameters were calculated using noncompartmental analysis. Thirty-two children (n = 10 in cohorts 1 and 2, n = 12 in cohort 3) were enrolled; the median age was 12 years (range 7-17 years), and the median weight was 42.2 kg (range 19.3-78 kg). The median oral TRE dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for cohorts 1, 2, and 3, respectively). The TRE concentration versus time profile demonstrated a peak concentration at a median of 3.8 hours with wide variability. In cohort 1, oral dosing led to higher peak (5.9 ng/mL) and lower trough (1 ng/mL) concentrations than parenteral (peak 5.4 ng/mL and trough 4.2 ng/mL), but a lower mean concentration (3.61 vs. 4.46 ng/mL), likely due to variable metabolism and noncomparable dosing. Both the area under the curve and average concentration were linearly correlated with oral TRE dose and dose normalized to body weight, but not with weight or age alone. In pediatric patients, an increased oral TRE dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.
Asunto(s)
Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Presión Arterial/efectos de los fármacos , Epoprostenol/análogos & derivados , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar/efectos de los fármacos , Administración Oral , Adolescente , Factores de Edad , Antihipertensivos/sangre , Niño , Esquema de Medicación , Epoprostenol/administración & dosificación , Epoprostenol/sangre , Epoprostenol/farmacocinética , Femenino , Humanos , Masculino , Modelos Biológicos , Hipertensión Arterial Pulmonar/sangre , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Resultado del Tratamiento , Estados UnidosRESUMEN
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.
Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Mesenterio/cirugía , Anciano , Dinamarca/epidemiología , Procedimientos Quirúrgicos del Sistema Digestivo/estadística & datos numéricos , Epoprostenol/sangre , Femenino , Rubor/sangre , Rubor/etiología , Humanos , Hipotensión/sangre , Hipotensión/etiología , Complicaciones Intraoperatorias/sangre , Complicaciones Intraoperatorias/epidemiología , Complicaciones Intraoperatorias/etiología , Masculino , Persona de Mediana Edad , Morbilidad , Síndrome , Taquicardia/sangre , Taquicardia/etiologíaRESUMEN
Aspirin eugenol ester (AEE) is a novel compound that is formed from the esterification of aspirin (acetylsalicylic acid (ASA)) and eugenol. This study aimed to investigate the effects of AEE on blood stasis in rats and to characterize the underlying mechanisms using a plasma metabolomic study. The results indicate that AEE and ASA could modulate whole blood viscosity (WBV), plasma viscosity (PV), blood coagulation parameters, platelet count, platelet aggregation, lactate dehydrogenase (LDH), creatinine (CR) and the levels of thromboxane A2 (TXA2) and 6-keto prostaglandin F1α (6-keto-PGF1α). The metabolic profiles of the plasma samples from all groups were clearly separated in the score plots. Nineteen potential metabolites were selected and identified, and disordered levels of these metabolites could be regulated by AEE and ASA. Pathway analysis showed that the mechanism of action of AEE on blood stasis might be principally related to the metabolism of amino acid, fatty acid, energy and glycerophospholipid. The above results indicate that AEE protected the rats against blood stasis, and that this effect might have been caused by the anticoagulation activity of AEE and its abilities to maintain a balance between TXA2 and PGI2, reduce blood viscosity, inhibit platelet aggregation and normalize the plasma metabolic profile.
Asunto(s)
Aspirina/análogos & derivados , Sangre/efectos de los fármacos , Eugenol/análogos & derivados , Enfermedades Hematológicas/tratamiento farmacológico , Metabolómica/métodos , Animales , Aspirina/administración & dosificación , Aspirina/farmacología , Análisis Químico de la Sangre , Coagulación Sanguínea/efectos de los fármacos , Viscosidad Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Epoprostenol/sangre , Eugenol/administración & dosificación , Eugenol/farmacología , Femenino , Enfermedades Hematológicas/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Ratas , Tromboxano A2/sangreRESUMEN
This study evaluated the pharmacokinetics of intravenous (IV) and subcutaneous (SC) treprostinil in pediatric patients with pulmonary vascular disease, and compared them with existing adult data from a similar cohort. Blood samples were collected from pediatric patients receiving steady-state IV or SC treprostinil and were assessed for plasma treprostinil concentration using liquid chromatography and tandem mass spectrometry. Forty participants, 15 receiving IV and 25 receiving SC treprostinil, were included in the analysis. Age ranged from 0.1 to 15.6 years. The median dose of treprostinil was 45.5 ng·kg·min with a range of 8-146 ng·kg·min. There was a linear relationship between treprostinil dose and plasma concentration with an R of 0.57. On average, there were higher blood concentrations per given dose of IV treprostinil compared with those per given dose of SC, but the difference was not significant. Compared with adult data, the slope of the pediatric data was similar, but the y-intercept was significantly lower. Additionally, the concentration per dose ratio was significantly higher in adults compared with children. Pediatric patients have significantly lower average blood concentrations of treprostinil per given dose compared with adults, and higher, but not significantly so, blood concentrations when treprostinil is administered IV as compared with SC administration.
Asunto(s)
Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Epoprostenol/análogos & derivados , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Adolescente , Factores de Edad , Antihipertensivos/sangre , Niño , Preescolar , Cromatografía Liquida , Estudios Transversales , Monitoreo de Drogas , Epoprostenol/administración & dosificación , Epoprostenol/sangre , Epoprostenol/farmacocinética , Femenino , Humanos , Lactante , Infusiones Intravenosas , Infusiones Subcutáneas , Masculino , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/fisiopatología , Espectrometría de Masas en Tándem , Estados UnidosAsunto(s)
Drenaje/métodos , Mucosa Intestinal/cirugía , Pancreatitis/cirugía , Paracentesis/métodos , Enfermedad Aguda , Animales , Epoprostenol/sangre , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/lesiones , Microcirculación , Pancreatitis/sangre , Pancreatitis/patología , Ratas , Índice de Severidad de la Enfermedad , Tromboxano A2/sangreRESUMEN
Treprostinil diolamine is the first oral dosage preparation of a prostacyclin analogue for use in treatment naive pulmonary arterial hypertension (PAH). This case series and review of the available literature describes the experience of patients with PAH receiving treprostinil by intravenous (IV), subcutaneous (SQ), or inhalation route who were transitioned to treprostinil diolamine. At our institution, 3 patients were transitioned to treprostinil diolamine who received treprostinil administered by each of the alternative routes: IV, SQ, and inhalation. All patients tolerated the transition without significant worsening of disease end points. In the literature, 5 additional reports representing 48 patients were transitioned to treprostinil diolamine from an alternate route of administration. A majority (92%) of patients were hospitalized during the cross-titration phase and tolerated the transition without changes in disease markers or significant adverse effect. Six (13%) patients required reinitiation of parenteral therapy due to clinical decline. The most common dosing frequency utilized for treprostinil diolamine was 3 times per day. In patients with stable PAH receiving parenteral or inhaled treprostinil, a transition to treprostinil diolamine was a safe approach in a highly select population meeting clinical end points. Additional studies are required to further describe this clinical strategy before accepted in clinical practice.
Asunto(s)
Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Epoprostenol/análogos & derivados , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/tratamiento farmacológico , Administración por Inhalación , Administración Oral , Adulto , Epoprostenol/administración & dosificación , Epoprostenol/sangre , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Epoprostenol/sangre , Rubor , Neoplasias Gastrointestinales/cirugía , Tracto Gastrointestinal/cirugía , 6-Cetoprostaglandina F1 alfa/metabolismo , Adolescente , Adulto , Anciano , Anestesia , Arterias/patología , Cara , Femenino , Neoplasias Gastrointestinales/complicaciones , Hemodinámica , Humanos , Rayos Láser , Hígado/cirugía , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/métodos , Páncreas/cirugía , Complicaciones Posoperatorias , Piel/irrigación sanguínea , Estómago/cirugía , Síndrome , Resistencia Vascular , Vasodilatación , Adulto JovenRESUMEN
Beraprost sodium is an oral prostacyclin analog that was first approved in 1992 (Japan) for the treatment of peripheral vascular disorders. It is administered orally as a tablet available in strength 20 µg. In this paper, we described a liquid chromatography tandem mass spectrometry method that was developed for the quantification of beraprost in human plasma with high sensitivity at picogram per milliliter concentration. The method had been validated in terms of selectivity, sensitivity, accuracy and precision, matrix effect, linearity, recovery and carry-over according to the Guideline on Bioanalytical Validation from the European Medicines Agency. The standard calibration curve for beraprost was 9.5-1419 pg/mL. This method has been applied successfully to a bioequivalence study with 60 µg of beraprost (three tablets) in 29 healthy volunteers. The results showed that the two formulations of beraprost are bioequivalent.
Asunto(s)
Cromatografía Liquida/métodos , Epoprostenol/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Epoprostenol/sangre , Epoprostenol/química , Epoprostenol/farmacocinética , Humanos , Modelos Lineales , Inhibidores de Agregación Plaquetaria/sangre , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Equivalencia TerapéuticaRESUMEN
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.
Asunto(s)
Flavonoides/farmacología , Infarto del Miocardio/prevención & control , Sustancias Protectoras/farmacología , Animales , Cromatografía Líquida de Alta Presión , Forma MB de la Creatina-Quinasa/sangre , Ensayo de Inmunoadsorción Enzimática , Epoprostenol/sangre , Genes bcl-2 , Hemodinámica/efectos de los fármacos , L-Lactato Deshidrogenasa/sangre , Malondialdehído/análisis , Distribución Aleatoria , Ratas Sprague-Dawley , Valores de Referencia , Reproducibilidad de los Resultados , Superóxido Dismutasa/análisis , Tromboxano A2/sangre , Resultado del Tratamiento , Proteína X Asociada a bcl-2/análisisRESUMEN
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.
Asunto(s)
Broncodilatadores/farmacología , Endotelina-1/sangre , Epoprostenol/sangre , Óxido Nítrico/farmacología , Embolia Pulmonar/sangre , Embolia Pulmonar/tratamiento farmacológico , Tromboxano A2/sangre , Troponina I/sangre , Enfermedad Aguda , Administración por Inhalación , Animales , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Femenino , Masculino , Embolia Pulmonar/patología , Conejos , Distribución Aleatoria , Valores de Referencia , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Animales , Flavonoides/farmacología , Sustancias Protectoras/farmacología , Infarto del Miocardio/prevención & control , Valores de Referencia , Superóxido Dismutasa/análisis , Tromboxano A2/sangre , Ensayo de Inmunoadsorción Enzimática , Distribución Aleatoria , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión , Epoprostenol/sangre , Resultado del Tratamiento , Ratas Sprague-Dawley , Genes bcl-2 , Forma MB de la Creatina-Quinasa/sangre , Proteína X Asociada a bcl-2/análisis , Hemodinámica/efectos de los fármacos , L-Lactato Deshidrogenasa/sangre , Malondialdehído/análisisRESUMEN
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.
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Animales , Masculino , Femenino , Conejos , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/sangre , Tromboxano A2/sangre , Broncodilatadores/farmacología , Epoprostenol/sangre , Endotelina-1/sangre , Troponina I/sangre , Óxido Nítrico/farmacología , Embolia Pulmonar/patología , Valores de Referencia , Factores de Tiempo , Administración por Inhalación , Ensayo de Inmunoadsorción Enzimática , Distribución Aleatoria , Regulación hacia Abajo , Enfermedad Aguda , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
It has long been known that chronic metabolic disease is associated with a parallel increase in the risk for developing peripheral vascular disease. Although more clinically relevant, our understanding about reversing established vasculopathy is limited compared with our understanding of the mechanisms and development of impaired vascular structure/function under these conditions. Using the 13-wk-old obese Zucker rat (OZR) model of metabolic syndrome, where microvascular dysfunction is sufficiently established to contribute to impaired skeletal muscle function, we imposed a 7-wk intervention of chronic atorvastatin treatment, chronic treadmill exercise, or both. By 20 wk of age, untreated OZRs manifested a diverse vasculopathy that was a central contributor to poor muscle performance, perfusion, and impaired O2 exchange. Atorvastatin or exercise, with the combination being most effective, improved skeletal muscle vascular metabolite profiles (i.e., nitric oxide, PGI2, and thromboxane A2 bioavailability), reactivity, and perfusion distribution at both individual bifurcations and within the entire microvascular network versus responses in untreated OZRs. However, improvements to microvascular structure (i.e., wall mechanics and microvascular density) were less robust. The combination of the above improvements to vascular function with interventions resulted in an improved muscle performance and O2 transport and exchange versus untreated OZRs, especially at moderate metabolic rates (3-Hz twitch contraction). These results suggest that specific interventions can improve specific indexes of function from established vasculopathy, but either this process was incomplete after 7-wk duration or measures of vascular structure are either resistant to reversal or require better-targeted interventions. NEW & NOTEWORTHY We used atorvastatin and/or chronic exercise to reverse established microvasculopathy in skeletal muscle of rats with metabolic syndrome. With established vasculopathy, atorvastatin and exercise had moderate abilities to reverse dysfunction, and the combined application of both was more effective at restoring function. However, increased vascular wall stiffness and reduced microvessel density were more resistant to reversal. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/reversal-of-microvascular-dysfunction/ .
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Atorvastatina/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Síndrome Metabólico/terapia , Microcirculación/efectos de los fármacos , Microvasos/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Enfermedades Vasculares Periféricas/terapia , Condicionamiento Físico Animal/métodos , Esfuerzo Físico , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Epoprostenol/sangre , Hemodinámica/efectos de los fármacos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/patología , Síndrome Metabólico/fisiopatología , Microvasos/patología , Microvasos/fisiopatología , Modelos Cardiovasculares , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Enfermedades Vasculares Periféricas/sangre , Enfermedades Vasculares Periféricas/patología , Enfermedades Vasculares Periféricas/fisiopatología , Ratas Zucker , Flujo Sanguíneo Regional , Carrera , Tromboxano A2/sangre , Factores de TiempoRESUMEN
This study aimed to investigate the antihypertensive effect and possible mechanism of Dendrobium officinale flos on hypertensive rats induced by high glucose and high fat compound alcohol. The hypertensive models were successfully made by high-glucose and high-fat diet, with gradient drinking for 4 weeks, and then divided into model control group, valsartan (5.7 mg·kg⻹) positive control group and D. officinale flos groups (3ï¼1 g·kg⻹). After 6 weeks of treatment, the blood pressure of rats was measured regularly. After the last administration, endothelin-1 (ET-1), thromboxane B2 (TXB2), prostacyclin (PGI2) and nitric oxide (NO) were tested. Endothelial nitric oxide synthase (eNOS) expression and lesion status in thoracic aorta were detected. The vascular endothelium dependent dilation of the thoracic aorta was detected by the isolated vascular loop tension test. The results showed that D. officinale flos could significantly reduce systolic blood pressure and mean arterial pressure in hypertensive rats, inhibit the thickening of thoracic aorta and the loss of endothelial cells, reduce plasma content of ET-1 and TXB2, and increase the content of PGI2 and NO. After long-term administration, vascular endothelium dependent dilation of the thoracic aorta was significantly increased, and could be blocked by the eNOS inhibitor (L-NAME) and increase the expression of eNOS. Therefore, D. officinale flos has an obvious antihypertensive effect on high glucose and high fat compound alcohol-induced hypertensive rats. Its mechanism may be correlated with the improvement of vascular diastolic function by protecting vascular endothelial cells, and finally resist hypertension.
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Antihipertensivos/farmacología , Dendrobium/química , Medicamentos Herbarios Chinos/farmacología , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Animales , Presión Sanguínea , Dieta Alta en Grasa , Endotelina-1/sangre , Epoprostenol/sangre , Glucosa , Hipertensión/inducido químicamente , Óxido Nítrico/sangre , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Proteínas de Dominio T Box/sangre , VasodilataciónRESUMEN
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.
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Hipertensión Pulmonar/prevención & control , Factores Sexuales , Linfocitos T Reguladores/fisiología , Inhibidores de la Angiogénesis/farmacología , Animales , Antígeno B7-H1/análisis , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Enfermedad Crónica , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/metabolismo , Sistema Enzimático del Citocromo P-450/análisis , Sistema Enzimático del Citocromo P-450/metabolismo , Epoprostenol/antagonistas & inhibidores , Epoprostenol/sangre , Epoprostenol/metabolismo , Femenino , Hemo Oxigenasa (Desciclizante)/análisis , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Indoles/farmacología , Oxidorreductasas Intramoleculares/análisis , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Pulmón/metabolismo , Masculino , Prostaglandinas I/biosíntesis , Pirroles/farmacología , Ratas , Ratas Desnudas , Receptores de Estrógenos/análisis , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Linfocitos T Reguladores/inmunología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Preeclampsia is a serious complication of pregnancy characterized by the development of vasospasm, hypertension and often associated with proteinuria after the 20th week of gestation. Because termination of pregnancy results in the most efficacious resolution of preeclampsia, it is a leading cause of premature delivery worldwide. In pregnancy, 14,15-epoxyeicosatrienoic acids (EETs) have been shown to facilitate uterine blood flow during preeclampsia, in which the classic vasodilator agents such as nitric oxide and prostacyclin are reduced. EETs are converted to dihydroxyeicosatrienoic acids (DHETs) by the activity of soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH activity is increased in preeclampsia by measuring urinary 14,15-DHET in healthy and preeclamptic pregnant women. Urine samples were collected and incubated with or without ß-glucuronidase to enable the measurement of both the glucuronidated and free forms of 14,15-DHET, which were quantified using a 14,15-DHET ELISA. Levels of total (free+glucuronidated) 14,15-DHET, which is a measurement of EET-dependent sEH activity, were higher in urine samples obtained from preeclamptic women compared to healthy pregnant women. Considering the fact that free+glucuronidated 14,15-DHET levels are increased in urine of preeclamptic women, we hypothesize that sEH expression or activity is augmented in these patients, reducing EET and increasing blood pressure. Moreover we suggest that novel anti-hypertensive agents that target sEH might be developed as therapeutics to control high blood pressure in women with preeclampsia.