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Platelet endothelial cell adhesion molecule 1 (PECAM-1) is considered an antiplatelet molecule. Previously, we introduced a new parameter called the PECAM-1/thrombus ratio, which indicates the proportion of PECAM-1 in the thrombus and provides a precise description of human platelet activity (in vitro). The aim of this study was to determine whether the PECAM-1/thrombus ratio could serve as a predictive factor for bleeding events during off-pump coronary artery bypass grafting (OPCAB). To achieve this, we collected blood samples from 20 patients scheduled to undergo OPCAB surgery. We assessed the PECAM-1/thrombus ratio by evaluating thrombus formation on collagen fibers under flow conditions. Subsequently, we compared the ability of the PECAM-1/thrombus ratio in predicting bleeding risk with other methods that evaluate hemostasis activity. These methods included assessing platelet P-selectin secretion, platelet exposure of phosphatidylserine, plasma coagulation and fibrinolysis system activity, and thrombus formation using the T-TAS assay. Our findings revealed a positive correlation between the PECAM-1/thrombus ratio and the amount of blood component units transfused (BCUT) during the OPCAB surgery. Furthermore, BCUT did not show any significant correlation with other measured hemostasis parameters. This preliminary study suggests that the PECAM-1/thrombus ratio might be a good predictor of bleeding risk during the OPCAB procedure.
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Trombosis , Humanos , Coagulación Sanguínea , Puente de Arteria Coronaria , Hemorragia , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Trombosis/etiologíaRESUMEN
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are antihyperglycemic drugs that decrease mortality from cardiovascular diseases. However, their effects on hemostasis in the cardioprotective effects have not been evaluated. Therefore, the effects of canagliflozin (CANA, 100 mg/kg, p.o.) and dapagliflozin (DAPA, 10 mg/kg, p.o.) on the parameters of hemostasis were investigated in female and male normoglycemic and streptozotocin (180 mg/kg, i.p.)-induced diabetic mice. CANA and DAPA reduced platelet activity in thrombus in male and female mice both normoglycemic and diabetic. CANA decreased thrombus formation in diabetic male mice, and platelet activation to ADP in diabetic female and male mice. Activation of fibrinolysis was observed in female mice, both normoglycemic and diabetic. DAPA reduced thrombus formation in diabetic male and female mice, and decreased platelet activation to ADP and fibrin formation in diabetic male mice. DAPA increased fibrin formation in normoglycemic female mice and activated fibrinolysis in diabetic female mice. CANA and DAPA exerted sex-specific effects, which were more pronounced in hyperglycemia. The antithrombotic effect of CANA and DAPA was more noticeable in male mice and could be due to platelet inhibition. The effect on coagulation and fibrinolysis was not clear since an increased coagulation and fibrinolysis were observed only in female mice.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Masculino , Femenino , Animales , Ratones , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Ratones Obesos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Activación Plaquetaria , FibrinaRESUMEN
The aim of this study was to evaluate the effect of acute aldosterone (ALDO) administration on the vascular permeability of skin. ALDO was injected intradermally into rats, and vascular permeability was measured. Eplerenone (EPL), a selective mineralocorticoid receptor (MR) antagonist, was used. Skin biopsies were carried out for immunohistochemical (IHC) staining, and polymerase chain reactions were performed to analyze the expression of MR, 11ß-hydroxysteroid dehydrogenase type 2, von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), and zonula occludens 1. Our study showed the presence of MR in the rat skin vasculature for the first time. It was found that ALDO injection resulted in a more than 30% increase in vascular permeability and enhanced the endothelial exocytosis of vWF. The effect of ALDO diminished after EPL administration. An accumulation of vWF and a reduction in VEGF IHC staining were observed following chronic EPL administration. No effect of ALDO or EPL on the mRNA expression of the studied genes or skin structure was observed. The results suggest that ALDO increases vascular permeability in the skin via an MR-dependent mechanism. This effect of ALDO on skin microcirculation may have important therapeutic implications for diseases characterized by increased levels of ALDO and coexisting skin microangiopathy.
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Aldosterona , Permeabilidad Capilar , Aldosterona/metabolismo , Aldosterona/farmacocinética , Aldosterona/farmacología , Animales , Permeabilidad Capilar/efectos de los fármacos , Eplerenona , Antagonistas de Receptores de Mineralocorticoides , Ratas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor de von Willebrand/metabolismoRESUMEN
The aim of the study was to investigate in vivo whether the application of immobilized superoxide dismutase (SOD) and catalase (CAT) could enhance DNA repairing systems and reduce level of CPD (cyclobutane pyrimidine dimers) and 6-4PP ((6-4) pyrimidine-pyrimidone photoproducts), and whether the immobilization on gold (AuNPs) and silver (AgNPs) nanoparticles affects the outcome. The study presents secondary analysis of our previous research. Three-day application of SOD and CAT in all forms of solution decreased the levels of CPD and 6-4PP boosted by UV irradiation. The mRNA expression level of the nucleotide excision repair (NER) system genes (XPA, XPC, ERCC1, ERCC2, ERCC3, LIG1) increased after application of immobilized and free enzymes. Increased by UV irradiation, p53 mRNA expression level normalized with the enzyme application. In conclusion, application of free and immobilized antioxidant enzymes accelerates removal of harmful effects of UV radiation in the rat skin by increasing expression level of NER genes.
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Nanopartículas del Metal , Rayos Ultravioleta , Animales , Antioxidantes , ADN/genética , Daño del ADN , Reparación del ADN , Oro , ARN Mensajero , Ratas , Plata/farmacología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
Background In addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading to increased experimental thrombosis. Striatin is an intermediate in the rapid, nongenomic actions of ALDO. Striatin heterozygote knockout (Strn+/-) mice have salt sensitivity of blood pressure and mildly chronically increased ALDO levels. In addition, in humans, striatin polymorphic gene variants are associated with increased salt sensitivity of blood pressure. Thus, we hypothesized that striatin deficiency would be associated with an increased prothrombotic response. Methods and Results Strn+/ - mice and wild-type littermates were maintained on a liberal sodium diet (1.6%). We measured in vivo thrombus formation following laser-induced injury in cremaster arterioles using intravital microscopy. Mice were randomized to intravenous administration of ALDO or its vehicle. Acutely, ALDO increased thrombotic responses in wild-type mice (P<0.01) versus controls within minutes as determined by increased platelet accumulation and fibrin deposition at the site of laser injury. We then compared thrombus formation without ALDO administration in Strn+/- and wild-type mice. Strn+/- mice showed highly significant increases in laser-induced thrombosis (P<0.001), as shown by increased platelet accumulation and fibrin deposition. Interestingly, the response in the Strn+/- mice basally was far greater than the wild-type mice with ALDO administration, and ALDO administration produced no additional effect on thrombus responses in Strn+/- mice. Conclusions These results demonstrate a novel protective role of striatin in experimental thrombosis. Such a protective effect may be reduced in human striatin risk allele carriers, given the similar salt sensitivity of blood pressure in these individuals and Strn+/- mice.
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Hipertensión , Trombosis , Aldosterona/química , Animales , Proteínas de Unión a Calmodulina , Fibrina/química , Fibrina/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Cloruro de Sodio Dietético , Trombosis/genética , Factores de Transcripción/genéticaRESUMEN
In our previous study, we introduced the platelet endothelial cell adhesion molecule 1 (PECAM-1)/thrombus ratio, which is a parameter indicating the proportion of PECAM-1 in laser-induced thrombi in mice. Because PECAM-1 is an antithrombotic molecule, the higher the PECAM-1/thrombus ratio, the less activated the platelets. In this study, we used an extracorporeal model of thrombosis (flow chamber model) to verify its usefulness in the assessment of the PECAM-1/thrombus ratio in animal and human studies. Using the lipopolysaccharide (LPS)-induced inflammation model, we also evaluated whether the PECAM-1/thrombus ratio determined in the flow chamber (without endothelium) differed from that calculated in laser-induced thrombosis (with endothelium). We observed that acetylsalicylic acid (ASA) decreased the area of the thrombus while increasing the PECAM-1/thrombus ratio in healthy mice and humans in a dose-dependent manner. In LPS-treated mice, the PECAM-1/thrombus ratio decreased as the dose of ASA increased in both thrombosis models, but the direction of change in the thrombus area was inconsistent. Our study demonstrates that the PECAM-1/thrombus ratio can more accurately describe the platelet activation status than commonly used parameters such as the thrombus area, and, hence, it can be used in both human and animal studies.
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Activación Plaquetaria/fisiología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/fisiología , Animales , Aspirina/análisis , Plaquetas/metabolismo , Plaquetas/fisiología , Adhesión Celular , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Endotelio Vascular/citología , Femenino , Voluntarios Sanos , Humanos , Inflamación , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Trombosis/metabolismoRESUMEN
In our previous study, we showed that ellagitannin- and procyanidin-rich tormentil extract (TE) decreased experimental arterial thrombosis in normoglycemic rats through platelet inhibition. TE also slightly increased coagulation and attenuated fibrinolysis; however, these effects did not nullify the antithrombotic effect of TE. The present study aimed to assess whether TE exerts antithrombotic activity in streptozotocin (STZ)-induced diabetes, which is characterized by pre-existing increased coagulation and impaired fibrinolysis, in vivo and ex vivo thrombosis assays. TE (100, 200, or 400 mg/kg, p. o.) was administered for 14 days to STZ-induced diabetic rats and mice. TE at 100 mg/kg dose decreased the thrombus area in the mice model of laser-induced thrombosis through its potent antiplatelet effect. However, TE at 200 mg/kg dose increased thrombus weight in electrically induced arterial thrombosis in rats. The prothrombotic effect could be due to increased coagulation and attenuated fibrinolysis. TE at 400 mg/kg dose also improved vascular functions, which was mainly reflected as an increase in the arterial blood flow, bleeding time prolongation, and thickening of the arterial wall. However, TE at 400 mg/kg dose did not exert antithrombotic effect. Summarizing, the present results show that TE may exert multidirectional effects on hemostasis in STZ-induced diabetic rats and mice. TE inhibited platelet activity and improved endothelial functions, but it also showed unfavorable effects by increasing the activity of the coagulation system and by inhibiting fibrinolysis. These contrasting effects could be the reason for model-specific influence of TE on the thrombotic process in STZ-induced diabetes.
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We investigated the role of aldosterone (ALDO) in the development of arterial thrombosis in streptozotocin-induced diabetic rats. To evaluate the effect of endogenous ALDO, the rats underwent adrenalectomy (ADX). ADX reduced the development of arterial thrombosis. A 1 h infusion of ALDO (30 µg/kg/h) enhanced thrombosis in adrenalectomized rats, while this effect was potentiated in diabetic rats. ALDO shortened bleeding time, increased plasma levels of tissue factor (TF) and plasminogen activator inhibitor, decreased plasma level of nitric oxide (NO) metabolites, and increased oxidative stress. Moreover, 2 h incubation of human umbilical vein endothelial cells (HUVECs) with ALDO (10-7 M) disrupted hemostatic balance in endothelial cells in normoglycemia (glucose 5.5 mM), and this effect was more pronounced in hyperglycemia (glucose 30 mM). We demonstrated that the acute ALDO infusion enhances arterial thrombosis in rats and hyperglycemia potentiates this prothrombotic effect. The mechanism of ALDO action was partially mediated by mineralocorticoid (MR) and glucocorticoid (GR) receptors and related to impact of the hormone on primary hemostasis, TF-dependent coagulation cascade, fibrinolysis, NO bioavailability, and oxidative stress balance. Our in vitro study confirmed that ALDO induces prothrombotic phenotype in the endothelium, particularly under hyperglycemic conditions.
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Aldosterona/efectos adversos , Aldosterona/uso terapéutico , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/etiología , Animales , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Ratas , Ratas Wistar , Trombosis/etiología , Trombosis/fisiopatologíaRESUMEN
The hemostasis system is often affected by complications associated with cardiovascular diseases, which results in thromboembolic events. Compounds of plant origin and plant extracts are considered as a promising source of substances that could modulate the functioning of the hemostasis system and thus reduce the risk of thromboembolism. Among them, tannins, which are plant-origin compounds with potential effects in hemostasis, deserve a special mention. This paper describes the hemostasis-modifying ability of three groups of tannins, namely ellagitannins, gallotannins, and procyanidins. The review highlights the desirable as well as undesirable influence of tannins on specific components of hemostasis, namely platelets, coagulation system, fibrinolysis system, and endothelium, and the multidirectional effect of these compounds on the thrombotic process. Studies performed under normal and pathological conditions such as diabetes or hypercoagulation are described, and the pathophysiology-dependent action of tannins is also highlighted. Most of the studies presented in the paper were performed in vitro, and due to the low bioavailability of tannins more studies should be conducted in the future to understand their actual activity in vivo.
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Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.
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Presión Sanguínea/efectos de los fármacos , Cannabidiol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Arteria Pulmonar/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacos , Animales , Hipertensión Pulmonar/inducido químicamente , Masculino , Monocrotalina , Arteria Pulmonar/patología , Ratas , Ratas WistarRESUMEN
Aim: Superoxide dismutase (SOD) and catalase (CAT) immobilized on gold nanoparticles (AuNP) and silver nanoparticles (AgNP) nanoparticles were used to reduce UV radiation-induced oxidative stress in rat skin. Materials & methods: The antioxidant influence of the enzymes was investigated on level of malondialdehyde, 8-hydroksy-2'deoksyguanozine, myeloperoxidase, total antioxidant capacity, SOD2 and CAT activity and expression, and glutathione and glutathione peroxidase activity. Results: The application of immobilized SOD and CAT on UV-irradiated skin reduced malondialdehyde and 8-hydroksy-2'deoksyguanozine levels also SOD and CAT activity and expression increased. The tested enzymes influence glutathione peroxidase activity and level of total antioxidant capacity and glutathione. Conclusion: Immobilized enzymes increased the antioxidative potential of skin following UV irradiation.
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Antioxidantes/farmacología , Enzimas Inmovilizadas/farmacología , Estrés Oxidativo/efectos de los fármacos , Protectores contra Radiación/farmacología , Piel/efectos de los fármacos , Animales , Antioxidantes/química , Catalasa/química , Catalasa/farmacología , Enzimas Inmovilizadas/química , Glutatión/química , Oro/química , Humanos , Malondialdehído/química , Nanopartículas del Metal/química , Protectores contra Radiación/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Piel/patología , Piel/efectos de la radiación , Superóxido Dismutasa/química , Superóxido Dismutasa/farmacología , Rayos Ultravioleta/efectos adversosRESUMEN
The goal of the study was the assessment of heterogeneous platelet activation status in thrombus. In a ferric(III) chloride (FeCl3) thrombosis (intravital) model of C57BL/6 J mice, the area of irreversibly activated (phosphatidylserine (PS)-positive) platelets was assessed after 1-s exposure of a vessel to FeCl3. In a laser-induced thrombosis (intravital) model of GFP mice, the area of the thrombus composed of PS-negative platelets was evaluated. The ratio of the area of PECAM-1 to the area of the thrombus was used as a marker to assess the activity of PS-negative platelets. In the in vitro flow chamber model, the thrombus area (PS-negative and PS-positive platelets) and the platelet activation index (ratio of the area of PS-positive platelets to the area of thrombus) were determined. To assess platelet activation status with these models, acetylsalicylic acid (ASA) and iloprost (Ilo) were used. In the FeCl3 thrombosis, ASA (10 mg/kg, 100 mg/kg) decreased the area of PS-positive platelets. In the laser thrombosis, ASA (10 mg/kg) decreased the thrombus area, but the decrease in platelet activity was evident even at 3 mg/kg by an increased PECAM-1/thrombus ratio. In the flow chamber, ASA (0.02 mg/ml, 0.2 mg/ml) equally decreased the platelet activation index, whereas only at 0.2 mg/ml, it decreased the thrombus area. Ilo (3.6 ng/ml, 36 ng/ml) decreased the thrombus area but at 36 ng/ml increased the platelet activation index. We showed that intravital models and flow chamber provide a detailed assessment of platelet activation status and the mechanism of drug action.
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Modelos Animales de Enfermedad , Activación Plaquetaria , Trombosis , Animales , Aspirina/farmacología , Cloruros , Compuestos Férricos , Fibrinolíticos/farmacología , Proteínas Fluorescentes Verdes/genética , Iloprost/farmacología , Rayos Láser , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Ratas Wistar , Trombosis/etiologíaRESUMEN
An increase in aldosterone levels positively correlates with an increased risk of acute cardiovascular thrombotic events. The aim of the study was to determine the mechanism of action of prothrombotic aldosterone focusing on the rapid effects of the hormone on platelets, coagulation, and fibrinolysis. A wide panel of advanced ex vivo and in vitro techniques was used for the evaluation of coagulation and fibrinolysis in aldosterone-treated rats. Additionally, two experimental mice models of thrombosis, which allowed for the intravital observation of the first stage of thrombus formation in real time, were used. Acute administration of aldosterone in rats increased the density of fibrin net and platelet aggregates in clots as well as reduced fibrinolysis. These effects were observed within 10â¯min and were partially suppressed by eplerenone. Moreover, acute administration of aldosterone in mice enhanced platelet accumulation at the site of endothelial injury induced by laser and increased the area of irreversibly activated platelets in FeCl3-induced thrombus. These results demonstrate that aldosterone acutely affects platelets, coagulation, and fibrinolysis, leading to an enhanced thrombosis. The aldosterone effects were mediated partially via a mineralocorticoid receptor. The mechanism seems to involve non-genomic signaling since the effects were observed within a few minutes of aldosterone administration.
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Aldosterona/toxicidad , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/efectos de los fármacos , Fibrinólisis/efectos de los fármacos , Trombosis/inducido químicamente , Animales , Plaquetas/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Agregación Plaquetaria/efectos de los fármacos , Ratas Wistar , Trombosis/sangre , Factores de TiempoRESUMEN
Aldosterone, the main mineralocorticoid hormone, plays a crucial role in the regulation of electrolyte homeostasis and blood pressure. Although this role is undoubtedly important, it is not a hormonal action that attracts the most attention. Aldosterone seems to be very important as a local messenger in the pathology of cardiovascular diseases (CVD). In the last few years, the attention was focused on the correlation between raised aldosterone level and increased risk of cardiovascular events. It has been demonstrated that aldosterone contributes to fibrosis, inflammation, endothelial dysfunction, fibrinolytic disorders, and oxidative stress leading to CVD development and progression. It used to be thought that the effects of aldosterone are mediated via classic nuclear receptors - mineralocorticoid receptors (MRs). Now we know that the mechanism of aldosterone action in the cardiovascular system (CVS) is much more complex since experimental and clinical studies indicate that MR blockade may be not sufficient to abolish aldosterone-induced harmful effects in CVS. Thus, the involvement of some other than MR, receptors, and factors is suggested. Moreover, in addition to the generally known genomic action of aldosterone, which involves MR activation, the nongenomic pathways are postulated in the mode of hormone action. More and more attention is focused on the membrane-coupled receptors, which mediate the rapid effects of aldosterone and have been already confirmed in different cells and tissues of CVS. Therefore, this brief review summarizes recent findings about new sides of aldosterone action in CVS that could be potential targets for therapeutic intervention.
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Aldosterona/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Sistema Cardiovascular/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Electrólitos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Biosíntesis de Proteínas/efectos de los fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transducción de Señal/genética , Transcripción Genética/efectos de los fármacosRESUMEN
Weekly measurements of air 7Be concentrations (nâ¯=â¯769) were performed in the years 1992-2010 in Bialystok (north-eastern Poland) using gamma spectrometry. The arithmetic mean (AM) concentration of 7Be was 2.51â¯mBq m-3, and the median (M) was 2.24â¯mBq m-3 (range 0.47-7.81â¯mBq m-3). The observed 7Be concentrations were within the range of levels recorded in Europe. Typical seasonal variability was observed. Concentrations of 7Be in the warm season (May, June, July) were almost twice as high as those in the cold season (November, December, January). A correlation was found between weekly 7Be concentrations and mean weekly values of relative humidity, temperature, and wind speed throughout the observation period. Pearson's correlation coefficients were -0.63, pâ¯<â¯0.001; 0.477, pâ¯<â¯0.001; -0.288, pâ¯<â¯0.001, respectively. The correlation coefficient between sunspot number and mean annual 7Be concentrations in the air in the years 1992-2010 was -0.609.
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Contaminantes Radiactivos del Aire/análisis , Berilio/análisis , Monitoreo de Radiación , PoloniaRESUMEN
Potentilla species that have been investigated so far display pharmacological activity mainly due to the presence of polyphenols. Recently, it was shown that polyphenol-rich extract from rhizome of Potentilla erecta (tormentil extract) affects the metabolism of arachidonic acid and exerts both anti-inflammatory and anti-oxidant activities, suggesting a possible effect on thrombosis. Accordingly, the aim of the study was to evaluate the effect of tormentil extract on haemostasis in a rat model of thrombosis. Lyophilized water-methanol extract from P. erecta rhizome was administrated per os for 14 days in doses of 100, 200, and 400 mg/kg in a volume of 2 mL/kg in a 5% water solution of gummi arabici (VEH). In the in vivo experiment an electrically induced carotid artery thrombosis model with blood flow monitoring was used in Wistar rats. Collected blood samples were analyzed ex vivo functionally and biochemically for changes in haemostasis. Tormentil extract (400 mg/kg) significantly decreased thrombus weight and prolonged the time to carotid artery occlusion and bleeding time without changes in the blood pressure. In the ex vivo experiment tormentil extract (400 mg/kg) reduced thromboxane production and decreased t-PA activity, while total t-PA concentration, as well as total PAI-1 concentration and PAI-1 activity remained unchanged. Furthermore, tormentil extract (400 mg/kg) decreased bradykinin concentration and shortened the time to reach maximal optical density during fibrin generation. Prothrombin time, activated partial thromboplastin time, QUICK index, fibrinogen level, and collagen-induced aggregation remained unchanged. To investigate the involvement of platelets in the antithrombotic effect of tormentil, the extract was administrated per os for 2 days to mice and irreversible platelets activation after ferric chloride induced thrombosis was evaluated under intravital conditions using confocal microscopy system. In this model tormentil extract (400 mg/kg) significantly reduced platelet activation at the same extent as acetylsalicylic acid. Taken together, we have shown for the first time that tormentil extract inhibits arterial thrombosis in platelet- and endothelial-dependent mechanisms without hemodynamic changes. Further studies on the detailed mechanism of action of tormentil extract toward fibrinolysis and the kinin system should be carried out.
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INTRODUCTION: The aim of this study was to investigate the effects of plasma and tissue angiotensin-converting enzyme inhibitors (ACE-Is) against propofol-induced endothelial dysfunction and to elucidate the involved mechanisms in vitro. MATERIALS AND METHODS: We examined the effects of propofol (50 µM), quinaprilat and enalaprilat (10-5 M) on fibrinolysis (t-PA, PAI-1, TAFI antigen levels), oxidative stress parameters (H2O2 and MDA antigen levels and SOD and NADPH oxidase mRNA levels) and nitric oxide bioavailability (NO2/NO3 concentration and NOS expression at the level of mRNA) in human umbilical vein endothelial cells (HUVECs). RESULTS: We found that both ACE-Is promoted similar endothelial fibrinolytic properties and decreased oxidative stress in vitro. Propofol alone increased the release of antifibrinolytic and pro-oxidative factors from the endothelium and increased mRNA iNOS expression. We also found that the incubation of HUVECs in the presence of propofol following ACE-Is pre-incubation caused weakness of the antifibrinolytic and pro-oxidative potential of propofol and this effect was similar after both ACE-Is. CONCLUSIONS: This observation suggests that the studied ACE-Is exerted protective effects against endothelial cell dysfunction caused by propofol, independently of hemodynamics.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antifibrinolíticos/farmacología , Células Endoteliales de la Vena Umbilical Humana/patología , Estrés Oxidativo/efectos de los fármacos , Propofol/farmacología , Disponibilidad Biológica , Hemostasis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Oxidación-Reducción , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The renin-angiotensin-aldosterone system (RAAS) is more complex than it was originally regarded. According to the current subject knowledge, there are two main axes of the RAAS: (1) angiotensin-converting enzyme (ACE)-angiotensin II-AT1 receptor axis and (2) ACE2-angiotensin-(1-7)-Mas receptor axis. The activation of the first axis leads to deleterious effects, including vasoconstriction, endothelial dysfunction, thrombosis, inflammation, and fibrosis; therefore, blocking the components of this axis is a highly rational and commonly used therapeutic procedure. The ACE2-Ang-(1-7)-Mas receptor axis has a different role, since it often opposes the effects induced by the classical ACE-Ang II-AT1 axis. Once the positive effects of the ACE2-Ang-(1-7)-Mas axis were discovered, the alternative ways of pharmacotherapy activating this axis of RAAS appeared. This article briefly describes new molecules affecting the RAAS, namely: recombinant human ACE2, ACE2 activators, angiotensin-(1-7) peptide and non-peptide analogs, aldosterone synthase inhibitors, and the third and fourth generation of mineralocorticoid receptor antagonists. The results of the experimental and clinical studies are encouraging, which leads us to believe that these new molecules can support the treatment of cardiovascular diseases as well as cardiometabolic disorders.
Asunto(s)
Sistema Renina-Angiotensina/efectos de los fármacos , Aldosterona/fisiología , Angiotensina I/fisiología , Enzima Convertidora de Angiotensina 2 , Animales , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Humanos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Fragmentos de Péptidos/fisiología , Peptidil-Dipeptidasa A/efectos de los fármacos , Peptidil-Dipeptidasa A/fisiología , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Angiotensin converting enzyme inhibitors and propofol both exert hypotensive action and may affect hemostasis. We investigated the influence of quinapril and propofol on hemodynamics and hemostasis in renal-hypertensive rats with induced arterial thrombosis. Two-kidney, one clip hypertensive rats were treated with quinapril (3.0 mg/kg for 10 days), and then received propofol infusion (15 mg/kg/h) during ongoing arterial thrombosis. The hemodynamic and hemostatic parameters were assayed. Quinapril exerted a hypotensive effect increasing after propofol infusion. Quinapril showed an antithrombotic effect with the platelet adhesion reduction, fibrinolysis enhancement and oxidative stress reduction. Propofol did not influence thrombosis; however, it inhibited fibrinolysis and showed prooxidative action. The effect of propofol on fibrinolysis and oxidative stress was significantly lower in quinapril-pretreated rats. Mortality was increased among rats treated with both drugs together. Our study demonstrates that pretreatment with quinapril reduced the adverse effects of propofol on hemostasis. Unfortunately, co-administration of both drugs potentiated hypotension in rats, which corresponds to higher mortality.
Asunto(s)
Antifibrinolíticos/uso terapéutico , Hipertensión/tratamiento farmacológico , Oxidantes/farmacología , Propofol/uso terapéutico , Tetrahidroisoquinolinas/uso terapéutico , Trombosis/tratamiento farmacológico , Animales , Antifibrinolíticos/farmacología , Aorta/efectos de los fármacos , Aorta/enzimología , Aorta/fisiopatología , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/fisiopatología , Hemodinámica/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Masculino , NADPH Oxidasas/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Adhesividad Plaquetaria/efectos de los fármacos , Propofol/farmacología , Quinapril , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Análisis de Supervivencia , Tetrahidroisoquinolinas/farmacología , Trombosis/sangre , Trombosis/complicacionesRESUMEN
INTRODUCTION: We showed previously that the prothrombotic effect of one hour aldosterone (ALDO) infusion in rats was only partially mediated by the mineralocorticoid receptor (MR). Bearing in mind that ALDO potentiates the effects of angiotensin II (Ang II), in the present study we investigated the role of Ang II receptor type 1 - AT1 in acute ALDO prothrombotic action. MATERIALS AND METHODS: The experiments were performed in a stasis-induced venous thrombosis model in male Wistar, normotensive rats. ALDO (30µg/kg) was infused for 1h. Valsartan (VAL; 10mg/kg), a selective AT1 receptor antagonist, was administered in a single bolus injection before ALDO infusion. Eplerenone (EPL, 100mg/kg), a selective MR receptor antagonist, was administered per os before ALDO. Thrombus weight and incidences of thrombosis were assayed. Bleeding time and platelet adhesion to collagen were evaluated as primary hemostasis parameters. The plasma levels of some coagulation and fibrinolysis parameters, and plasma NO metabolite levels were assayed. RESULTS: AT1 blockade with valsartan significantly reduced ALDO-induced thrombosis expressed as a reduced thrombus mass (p<0.05 vs ALDO) and diminished the incidence of thrombosis. Valsartan reduced the ALDO-induced changes in bleeding time and platelet adhesion, as well as in coagulation, fibrinolysis, and NO metabolite levels. The effect of AT1 blockade in ALDO-induced thrombosis was similar to the effect of MR blockade. However, dual blockade of AT1 and MR showed no additional benefit. CONCLUSIONS: ALDO prothrombotic action is partially mediated via AT1 receptor in the mechanism involving enhanced platelet activation, induced coagulation, impaired fibrinolysis and reduced NO bioavailability.