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1.
Int J Biol Macromol ; 232: 123408, 2023 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-36709813

RESUMEN

Crotalus durissus snakebite represent 10 % of snakebite cases in Brazil, which cardiovascular disorders are associated with severe cases. Considering crotoxin (CTX) as the major venom component, the present study aimed to evaluate the hemodynamic alterations induced by CTX using in vivo and ex vivo approaches in a rat model. In vivo cardiac function parameters were analyzed from anesthetized rats treated with CTX or saline only (Sham), along with serum creatine kinase MB (CK-MB) and lung myeloperoxidase. From the same animals, hearts were isolated and functional parameters evaluated in Langendorff method ex vivo. CTX binding to myoblast cell line in vitro were evaluated using confocal microscopy and flow cytometry. CTX was capable of reducing arterial and diastolic blood pressure, heart rate, along with left ventricle pressure development or decay during systole (LVdP/dtmax and LVdP/dtmin) in vivo, however no differences were found in the ex vivo approach, showing that intrinsic heart function was preserved. In vitro, CTX binding to myoblast cell line was mitigated by hexamethonium, a nicotinic acetylcholine receptor antagonist. The present study has shown that CTX induce hemodynamic failure in rats, which can help improve the clinical management of cardiovascular alterations during Crotalus durissus snakebite.


Asunto(s)
Crotoxina , Mordeduras de Serpientes , Ratas , Animales , Crotoxina/farmacología , Presión Sanguínea , Brasil
2.
Nitric Oxide ; 115: 23-29, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34133975

RESUMEN

INTRODUCTION: The mechanical obstruction and pulmonary vasoconstriction are major determinants of the sudden right ventricular (RV) afterload increases observed during acute pulmonary thromboembolism (APT). Vasodilators and antioxidants agents have been shown to mitigate pulmonary hypertension. We examined whether sodium nitrite and the antioxidant tempol combination could be advantageous in an APT sheep model. METHODS: APT was induced in anesthetized sheep by autologous blood clots (250 mg/kg) into the right atrium. Thirty minutes after APT induction, the animals received a continuous infusion of tempol (1.0 mg/kg/min), increasing sodium nitrite infusion (5, 15, and 50 µmol/kg), or a simultaneous combination of both drugs. Saline was used as a control treatment. Hemodynamic measurements were carried out every 15 min. Also, whole blood nitrite and serum 8-isoprostanes levels were measured. RESULTS: APT induced sustained pulmonary hypertension, increased dp/dtmax, and rate pressure product (RPP). Nitrite or tempol treatments attenuated these increases (P < 0.05). When both drugs were combined, we found a robust reduction in the RV RPP compared with the treatments alone (P < 0.05). The sole nitrite infusion increased blood nitrite concentrations by 35 ± 6 µM (P < 0.05), whereas the nitrite and tempol combination produced higher blood nitrite concentrations by approximately 54 ± 7 µM. Tempol or nitrite infusions, both alone or combined, blunted the increases in 8-isoprostane concentrations observed after APT. CONCLUSIONS: Nitrite and tempol combination protects against APT-induced RV wall stress. The association of both drugs may offer an advantage to treat RV failure during severe APT.


Asunto(s)
Antioxidantes/farmacología , Óxidos N-Cíclicos/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Nitrito de Sodio/farmacología , Enfermedad Aguda , Animales , Antioxidantes/administración & dosificación , Óxidos N-Cíclicos/administración & dosificación , Ventrículos Cardíacos/metabolismo , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/metabolismo , Masculino , Ovinos , Nitrito de Sodio/administración & dosificación , Marcadores de Spin
3.
Life Sci ; 244: 117153, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31830479

RESUMEN

AIMS: Increased activity of calpain-1 and matrix metalloproteinase (MMP)-2 was observed in different models of arterial hypertension and contribute to thicken the left ventricle (LV) walls and to hypertrophy cardiac myocytes. MMP-2 activity may be regulated by calpain-1 via bioactive molecules activation such as transforming growth factor (TGF)-ß in cardiovascular diseases. This study analyzed whether calpain-1 causes cardiac hypertrophy and dysfunction by modulating the expression and activity of MMP-2 in renovascular hypertension. MAIN METHODS: Male Wistar rats were submitted to two kidneys, one clip (2K1C) model of hypertension or sham surgery and were treated with verapamil (VRP, 8 mg/kg/bid) by gavage from the second to tenth week post-surgery. Systolic blood pressure (SBP) was weekly assessed by tail-cuff plethysmography and morphological and functional parameters of LV were analyzed by echocardiography. MMP-2 activity was analyzed by in situ and gelatin zymography, while calpain-1 activity by caseinolytic assay. MMP-2, calpain-1, TGF-ß and MMP-14/TIMP-2 levels were identified in the LV by western blots. Fluorescence assays were performed to evaluate oxidative stress, MMP-2 and calpain-1 levels. KEY FINDINGS: SBP increased in 2K1C rats and was unaltered by VRP. However, VRP notably ameliorated hypertension-induced increase in LV thickness. VRP decreased hypertension-induced enhances in calpain-1 and MMP-2 activities, oxidative stress and mature TGF-ß levels. Treatment with VRP also decreased the accentuated MMP-14/TIMP-2 levels in 2K1C. SIGNIFICANCE: Treatment with VRP decreases calpain-1 and MMP-2 activities and also reduces TGF-ß and MMP-14/TIMP-2 levels in the LV of hypertensive rats, thus contributing to ameliorate cardiac hypertrophy.


Asunto(s)
Calpaína/metabolismo , Cardiomegalia/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/complicaciones , Metaloproteinasa 2 de la Matriz/metabolismo , Remodelación Ventricular/efectos de los fármacos , Verapamilo/farmacología , Animales , Calpaína/genética , Cardiomegalia/etiología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Ratas , Ratas Wistar , Vasodilatadores/farmacología
4.
J Mol Cell Cardiol ; 134: 40-50, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31226341

RESUMEN

Although nitrite improves vascular function and lowers blood pressure, its cardiac effects are not completely known. We investigated whether nitrite improves the cardiac function in normotensive and in hypertensive rats. Two-kidney, one-clip hypertension model (2K1C) was induced in Wistar rats. Blood pressure was evaluated by tail-cuff plethysmography over 6 weeks. By the end of week 2, hypertensive and normotensive rats received nitrite (daily dose of 1 or 15 mg/kg) by gavage for 4 weeks. Cardiac morphology and function were performed by transthoracic echocardiography. Intrinsic heart function was evaluated using the isolated heart model (Langendorff's preparation). Starling curves were generated under nitrite (1 µmol/L) and/or ascorbate (1 mmol/L) or vehicle. Cardiac tissue was collected and snap frozen for biochemical analysis. Nitrite treatment (15 mg/kg) lowered both systolic blood pressure and the increases in left ventricular (LV) mass found in 2K1C rats (P < .05). In addition, nitrite treatment restored the decreased cardiac output in 2K1C rats (P < .05) and improved the cardiac function. These findings were associated with increased nitrite, S-nitrosothiols, and protein S-nitrosylation (all P < .05) assessed in heart tissue. The cardiac effects of nitrite were further investigated in the isolated heart model, and nitrite infusion (1 µmol/L) enhanced cardiac contractility and relaxation. This infusion increased S-nitrosothiols concentrations and protein S-nitrosylation in the heart. Ascorbate completely blunted all nitrite-induced effects. These findings show that treatment with oral nitrite improves cardiac function by mechanisms involving increased S-nitrosothiols generation and S-nitrosylation of cardiac proteins. Pharmacological strategies promoting cardiac S-nitrosylation may be useful to improve myocardial function in heart diseases.


Asunto(s)
Cardiomiopatías/etiología , Cardiomiopatías/prevención & control , Hipertensión/complicaciones , Miocardio/metabolismo , Nitratos/metabolismo , Nitrito de Sodio/farmacología , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/metabolismo , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Miocardio/patología , Nitrosación/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Nitrito de Sodio/uso terapéutico
5.
Physiol Rep ; 5(19)2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29038355

RESUMEN

Although extensively used for the study of left ventricular function, limited experience exists with the isolated heart model in the evaluation of right ventricular (RV) function. In particular, no published experience exists with this tool in sugen/hypoxia-induced pulmonary hypertension (SuHx-PH), a frequently used model of severe and progressive PH We sought to characterize markers of RV contractile and diastolic function in SuHx-PH and to establish their relationship with markers of maladaptive RV remodeling. Hearts were excised from anesthetized Sprague Dawley rats with or without SuHx-PH and perfused via the aorta using a Langendorff preparation. We explored the Frank-Starling relationship of RV function (RV developed pressure, dP/dtmax, and dP/dtmin; all normalized to RV mass) by increasing RV end-diastolic pressure (RVEDP) from 0 to 40 mmHg. Functional studies were complemented by quantification of RV pro-apoptotic signaling (bcl2/bax), procontractile signaling (apelin), and stress response signaling (p38MAPK activation). Pearson's correlation analysis was performed for functional and biochemical parameters. SuHx-RVs exhibited severe RV dysfunction with marked hypertrophy and decreased echocardiographic cardiac output. For any given RVEDP, SuHx-RVs demonstrated less developed pressure and lower dP/dtmax, as well as less pronounced dP/dtmin, suggestive of decreased contractile and diastolic function. SuHx-RVs exhibited decreased bcl2/bax ratios, apelin expression, and p38MAPK activation. Bcl2/bax and apelin RNA abundance correlated positively with RV developed pressure and dP/dtmax and negatively with dP/dtmin p38MAPK activation correlated positively with RV developed pressure. We conclude that SuHx-RVs exhibit severe contractile and diastolic dysfunction. Increased pro-apoptotic signaling and attenuated procontractile and stress response signaling may contribute to these functional alterations.


Asunto(s)
Corazón/fisiopatología , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Contracción Miocárdica , Disfunción Ventricular Derecha , Animales , Apelina/genética , Apelina/metabolismo , Diástole , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipoxia/etiología , Indoles/toxicidad , Preparación de Corazón Aislado , Masculino , Miocardio/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirroles/toxicidad , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
6.
Thromb Res ; 155: 106-115, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28528289

RESUMEN

Changes in systemic redox balance can alter platelet activation and aggregation. Acute pulmonary embolism (PE) is a systematic inflammatory disease associated with mechanical shear stress, increased thrombin, catecholamines, serotonin and hemolysis, which cumulatively can hyperactivate platelets and accelerate their turnover. We tested the hypothesis that platelets from patients with moderately severe PE will show hyperstimulation and a pre-apoptotic phenotype associated with microparticles (MPs) in plasma. Blood for platelet respiration and thromboelastography (TEG) was obtained at diagnosis and 24h later from patients (n=76) with image-proven PE, SBP>90mmHg and right ventricular dysfunction demonstrated by echocardiogram or elevated biomarkers. Controls (n=12) were healthy volunteers. At diagnosis, platelets from PE patients had significantly elevated baseline oxygen consumption compared with controls, explained primarily by accelerated electron transport and oxygen wasting with no measurable extramitochondrial oxygen consumption. On thromboelastography, unstimulated thrombin-independent maximum amplitude was increased with PE, 19±14.1 vs.10.5±7.8mm in controls (p=0.002). Compared with controls, platelets from PE patients showed elevated mitochondrial reactive oxygen species with decreased mitochondrial Bcl-2 protein content and increased cytosolic cytochrome C, coincident with strong annexin V binding, P selectin release from lysed platelets and in plasma MPs compared to controls (p<0.05). These results show evidence of platelet hyperactivation and apoptosis in patients with acute PE, and provide preliminary theoretical basis for further exploration of platelet inhibition in patients with more severe PE.


Asunto(s)
Apoptosis , Activación Plaquetaria , Embolia Pulmonar/sangre , Embolia Pulmonar/complicaciones , Trombofilia/sangre , Trombofilia/complicaciones , Enfermedad Aguda , Adulto , Anciano , Coagulación Sanguínea , Plaquetas/metabolismo , Plaquetas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Estrés Oxidativo , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patología , Especies Reactivas de Oxígeno/metabolismo , Trombofilia/metabolismo , Trombofilia/patología
7.
Am J Pathol ; 187(4): 700-712, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28183533

RESUMEN

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.


Asunto(s)
Hipertensión Pulmonar/etiología , Embolia Pulmonar/complicaciones , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Cardiomegalia/sangre , Cardiomegalia/complicaciones , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Pruebas de Función Cardíaca , Hemodinámica/efectos de los fármacos , Hiperplasia , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Hipoxia/patología , Hipoxia/fisiopatología , Indoles/farmacología , Antígeno Ki-67/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Microesferas , Consumo de Oxígeno/efectos de los fármacos , Selectina-P/sangre , Presión Parcial , Condicionamiento Físico Animal , Inhibidor 1 de Activador Plasminogénico/sangre , Poliestirenos , Embolia Pulmonar/sangre , Embolia Pulmonar/fisiopatología , Pirroles/farmacología , Ratas Sprague-Dawley , Inhibidor Tisular de Metaloproteinasa-1/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Disfunción Ventricular/sangre , Disfunción Ventricular/complicaciones , Disfunción Ventricular/fisiopatología
8.
Comp Med ; 65(1): 54-61, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25730758

RESUMEN

Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO2 (98% ± 3% compared with 95% ± 1%), end-tidal CO2 (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE.


Asunto(s)
Anestesia/veterinaria , Anestésicos por Inhalación/farmacología , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Embolia Pulmonar/complicaciones , Embolia Pulmonar/fisiopatología , Disfunción Ventricular Derecha/etiología , Anestesia/mortalidad , Animales , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Cloralosa/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Isoflurano/farmacología , Porcinos
9.
J Cell Mol Med ; 17(12): 1588-97, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24199964

RESUMEN

Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 µg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ~185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.


Asunto(s)
Dobutamina/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Embolia Pulmonar/complicaciones , Embolia Pulmonar/tratamiento farmacológico , Disfunción Ventricular Derecha/complicaciones , Disfunción Ventricular Derecha/tratamiento farmacológico , Enfermedad Aguda , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Dobutamina/farmacología , Doxiciclina/farmacología , Doxiciclina/uso terapéutico , Electroforesis en Gel de Poliacrilamida , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Embolia Pulmonar/patología , Embolia Pulmonar/fisiopatología , Ovinos , Troponina I/sangre , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/fisiopatología
11.
Thromb Res ; 132(5): 578-83, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24083962

RESUMEN

INTRODUCTION: Acute pulmonary thromboembolism (APT) is a critical condition associated with acute pulmonary hypertension. Recent studies suggest that oxidative stress and hemolysis contribute to APT-induced pulmonary hypertension, possibly as a result of increased nitric oxide (NO) consumption. We hypothesized that the antioxidant tempol could attenuate APT-induced hemolysis, and therefore attenuate APT-induced increases in plasma NO consumption. MATERIALS AND METHODS: APT was induced in anesthetized sheep with autologous blood clots. The hemodynamic effects of tempol infused at 1.0mg/kg/min 30 min after APT were determined. Hemodynamic measurements were carried out every 15 min. To assess oxidative stress, serum 8-isoprostanes levels were measured by ELISA. Plasma cell-free hemoglobin concentrations and NO consumption by plasma samples were determined. An in vitro oxidative AAPH-induced hemolysis assay was used to further validate the in vivo effects of tempol. RESULTS: APT caused pulmonary hypertension, and increased pulmonary vascular resistance in proportion with the increases in 8-isoprostanes, plasma cell-free hemoglobin concentrations, and NO consumption by plasma (all P<0.05). Tempol attenuated the hemodynamic alterations by approximately 15-20% and blunted APT-induced increases in 8-isoprostanes, in cell-free hemoglobin concentrations, and the increases in NO consumption by plasma (P<0.05). Tempol dose-dependently attenuated AAPH-induced in vitro hemolysis (P<0.05). CONCLUSIONS: Our findings are consistent with the idea that antioxidant properties of tempol decrease APT-induced hemolysis and nitric oxide consumption, thus attenuating APT-induced pulmonary hypertension.


Asunto(s)
Antioxidantes/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hemólisis/efectos de los fármacos , Óxido Nítrico/sangre , Embolia Pulmonar/sangre , Embolia Pulmonar/tratamiento farmacológico , Animales , Hemodinámica/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Embolia Pulmonar/patología , Ovinos , Marcadores de Spin
12.
Crit Care Med ; 41(7): e118-24, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23478656

RESUMEN

OBJECTIVES: We examined whether experimental lung embolization with autologous blood clots or with the infusion of microspheres increase cell-free hemoglobin levels and nitric oxide consumption by plasma samples from anesthetized lambs. These parameters were also measured in patients with acute pulmonary thromboembolism at baseline conditions and after thrombolysis, and in healthy controls. DESIGN: Controlled animal and clinical studies. SETTING: University research laboratory and university hospital. SUBJECTS: Sheep and humans. INTERVENTIONS: Anesthetized lambs were embolized with intravenous injections of autologous blood clots or repeated injections of 300 µm microspheres. Control animals received saline. Blood samples were drawn from patients with acute pulmonary thromboembolism at baseline conditions and after thrombolytic therapy with streptokinase or alteplase. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements were performed and plasma cell-free hemoglobin concentrations were measured. A nitric oxide consumption assay was used to measure nitric oxide consumption by plasma samples. Embolization with blood clots or microspheres increased mean pulmonary artery pressure from ~15 to ~40 mm Hg in lambs. Both plasma hemoglobin concentrations and nitric oxide consumption increased in proportion to the hemodynamic alterations and correlated significantly. Patients with acute pulmonary thromboembolism had higher plasma hemoglobin concentrations and nitric oxide consumption than healthy controls. Thrombolysis with streptokinase or alteplase further increased both parameters, which peaked 1-3 days after thrombolysis. CONCLUSIONS: Our results show consistent evidence indicating a new mechanism involving increased hemoglobin decompartmentalization and augmented nitric oxide consumption, possibly contributing to the hemodynamic derangement of acute pulmonary thromboembolism.


Asunto(s)
Hemoglobinas/metabolismo , Óxido Nítrico/metabolismo , Embolia Pulmonar/fisiopatología , Animales , Modelos Animales de Enfermedad , Hemodinámica , Masculino , Embolia Pulmonar/metabolismo , Ovinos
13.
Curr Drug Targets ; 14(3): 344-52, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23316966

RESUMEN

Acute pulmonary embolism is a critical condition associated with increased mortality. Lung embolization causes acute pulmonary hypertension and right ventricle afterload. Global heart ischemia supervenes and may lead to severe shock and death. In this article, we reviewed current literature supporting the idea that abnormal matrix metalloproteinase (MMP) activity contributes to acute pulmonary embolism-induced hemodynamic changes. While low MMP levels are usually found in normal lung tissues, it is well known that inflammation and lung injury increase MMP expression and activity. This is probably due to recruitment and migration of inflammatory cells from the circulation to lung tissues. In addition, recent studies have shown increased MMP levels and activity in the right ventricle from animals with acute pulmonary embolism. Such increases in proteolytic activity were associated with increased cardiac troponin I in serum, suggesting a possible role for MMPs in cardiomyocyte injury during acute pulmonary embolism. These alterations have justified the use of doxycycline as an MMP inhibitor in acute pulmonary embolism. We review current evidence indicating that MMPs are targets in this critical condition. MMP inhibition apparently exerts antihypertensive effects and protects against cardiomyocyte injury caused by acute pulmonary embolism.


Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Metaloproteinasas de la Matriz/fisiología , Embolia Pulmonar/tratamiento farmacológico , Enfermedad Aguda , Animales , Biomarcadores , Proteínas de Unión a Ácidos Grasos/sangre , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Miocitos Cardíacos/patología , Péptido Natriurético Encefálico/sangre , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/enzimología , Embolia Pulmonar/etiología , Troponina/sangre
14.
Basic Clin Pharmacol Toxicol ; 112(2): 103-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22913757

RESUMEN

Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair ß-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during ß(1) -adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 µg/kg/min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP-2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/dt(max) , and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of ß-adrenoreceptors.


Asunto(s)
Dobutamina/farmacología , Doxiciclina/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Hemodinámica , Humanos , Infusiones Intravenosas , Masculino , Metaloproteinasa 2 de la Matriz/administración & dosificación , Receptores Adrenérgicos beta 1/efectos de los fármacos , Proteínas Recombinantes , Ovinos
15.
Int J Cardiol ; 165(1): 165-73, 2013 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-21917342

RESUMEN

BACKGROUND: Increased oxidative stress upregulates matrix metalloproteinases (MMPs) and transforming grow factor (TGF-ß), which are involved in hypertensive cardiac remodeling. We tested the hypothesis that tempol (an antioxidant) could prevent these alterations in two-kidney, one-clip (2K1C) hypertension. METHODS: Sham-operated or hypertensive rats were treated with tempol (18 mg.kg(-1)day(-1) or vehicle) for 8 weeks. Systolic blood pressure was monitored weekly. At the end of the treatment, a catheter was inserted into the left carotid artery and into the left ventricle (LV) to assess arterial blood pressure and contractile function. Morphometry of the LV was carried out in hematoxylin/eosin sections and fibrosis was assessed in picrosirius red-stained sections. Cardiac TGF-ß level was evaluated by immunofluorescence. Cardiac MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Cardiac superoxide production was evaluated by dihydroethidium probe. RESULTS: Tempol treatment attenuated 2K1C-induced hypertension and reversed the contractile dysfunction in 2K1C rats. Cardiac hypertrophy was ameliorated by antioxidant treatment. Hypertensive rats showed increased cardiac MMP-2 levels, however tempol did not decrease MMP-2 levels. Increased TGF-ß level, total gelatinolytic activity and oxidative stress were found in untreated 2K1C rats. Tempol treatment decreased oxidative stress, TGF-ß levels, and gelatinolytic activity in 2K1C rats to control levels. CONCLUSIONS: Tempol blunted the increases in TGF-ß, the proteolytic imbalance, and the morphological and functional alterations found in 2K1C-induced cardiac hypertrophy. These findings are consistent with the idea that antioxidants may help to prevent hypertension-induced cardiac hypertrophy.


Asunto(s)
Cardiomegalia/prevención & control , Cardiotónicos/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hipertensión/prevención & control , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Metaloproteinasas de la Matriz/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Cardiomegalia/metabolismo , Cardiomegalia/patología , Cardiotónicos/farmacología , Óxidos N-Cíclicos/farmacología , Hipertensión/metabolismo , Hipertensión/patología , Masculino , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteinasas de la Matriz/biosíntesis , Ratas , Ratas Wistar , Marcadores de Spin , Factor de Crecimiento Transformador beta/biosíntesis , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología
16.
Naunyn Schmiedebergs Arch Pharmacol ; 385(7): 685-96, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22552729

RESUMEN

Increased reactive oxygen species (ROS) promote matrix metalloproteinase (MMP) activities and may underlie cardiomyocyte injury and the degradation of cardiac troponin I (cTI) during acute pulmonary thromboembolism (APT). We examined whether pretreatment or therapy with tempol (a ROS scavenger) prevents MMP activation and cardiomyocyte injury of APT. Anesthetized sheep received tempol infusion (1.0 mg kg(-1) min(-1), i.v.) or saline starting 30 min before or 30 min after APT (autologous blood clots). Control animals received saline. Hemodynamic measurements were performed. MMPs were studied in the right ventricle (RV) by gelatin zymography, fluorimetric activity assay, and in situ zymography. The ROS levels were determined in the RV and cTI were measured in serum samples. APT increased the pulmonary arterial pressure and pulmonary vascular resistance by 146 and 164%, respectively. Pretreatment or therapy with tempol attenuated these increases. While APT increased RV + dP/dt (max), tempol infusions had no effects. APT increased RV MMP-9 (but not MMP-2) levels. In line with these findings, APT increased RV MMP activities, and this finding was confirmed by in situ zymography. APT increased the RV ROS levels and tempol infusion, before or after APT, and blunted APT-induced increases in MMP-9 levels, MMP activities, in situ MMP activities, and ROS levels in the RV. cTI concentrations increased after APT, and tempol attenuated these increases. RV oxidative stress after APT increases the RV MMP activities, leading to the degradation of sarcomeric proteins, including cTI. Antioxidant treatment may prevent MMP activation and protect against cardiomyocyte injury after APT.


Asunto(s)
Antioxidantes/farmacología , Óxidos N-Cíclicos/farmacología , Embolia Pulmonar/tratamiento farmacológico , Animales , Antioxidantes/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Quimiotaxis , Óxidos N-Cíclicos/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Embolia Pulmonar/metabolismo , Embolia Pulmonar/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Ovinos , Marcadores de Spin , Troponina I/metabolismo
17.
Naunyn Schmiedebergs Arch Pharmacol ; 385(2): 211-7, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21964667

RESUMEN

The acute obstruction of pulmonary vessels by venous thrombi is a critical condition named acute pulmonary embolism (APE). During massive APE, severe pulmonary hypertension may lead to death secondary to right heart failure and circulatory shock. APE-induced pulmonary hypertension is aggravated by active pulmonary vasoconstriction. While blocking the effects of some vasoconstrictors exerts beneficial effects, no previous study has examined whether angiotensin II receptor blockers protect against the hemodynamic changes associated with APE. We examined the effects exerted by losartan on APE-induced hemodynamic changes. Hemodynamic evaluations were performed in non-embolized lambs treated with saline (n = 4) and in lambs that were embolized with silicon microspheres and treated with losartan (30 mg/kg followed by 1 mg/kg/h, n = 5) or saline (n = 7) infusions. The plasma and lung angiotensin-converting enzyme (ACE) activity were assessed using a fluorometric method. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 21 ± 2 mmHg and 375 ± 20 dyn s cm⁻5 m⁻², respectively (P < 0.05). Losartan decreased MPAP significantly (by approximately 15%), without significant changes in PVRI and tended to decrease cardiac index (P > 0.05). Lung and plasma ACE activity were similar in both embolized and non-embolized animals. Our findings show evidence of lack of activation of the renin-angiotensin system during APE. The lack of significant effects of losartan on the pulmonary vascular resistance suggests that losartan does not protect against the hemodynamic changes found during APE.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Losartán/uso terapéutico , Embolia Pulmonar/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Masculino , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/metabolismo , Embolia Pulmonar/complicaciones , Embolia Pulmonar/enzimología , Embolia Pulmonar/fisiopatología , Ovinos , Resistencia Vascular/efectos de los fármacos
18.
Eur J Pharmacol ; 670(2-3): 554-60, 2011 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-21946107

RESUMEN

We investigated whether atorvastatin has beneficial hemodynamic effects during acute pulmonary thromboembolism (APT) and whether sildenafil improves these effects. We studied the involvement of oxidative stress, matrix metalloproteinases (MMPs), and neutrophil activation. APT was induced with autologous blood clots (500 mg/kg) in anesthetized male lambs pretreated with atorvastatin (10 mg/kg/day, subcutaneously; 1 week) or vehicle (dimethyl sulfoxide 10% subcutaneously). Sildenafil (0.7 mg/kg intravenously) or saline infusions were performed 60 min after APT induction. Non-embolized control animals received saline. APT significantly increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) by approximately 310% and 258% respectively. While atorvastatin pretreatment attenuated these increases (~150% and 153%, respectively; P < 0.05), its combination with sildenafil was associated with lower increases in PVRI and MPAP (~32% and 36%, respectively). Gelatin zymography showed increased MMP-9 and MMP-2 levels in the bronchoalveolar lavage, and increased MMP-9 levels in plasma from embolized animals. Atorvastatin pretreatment attenuated bronchoalveolar lavage MMP-2 increases. The combination of drugs blunted the MMPs increases in bronchoalveolar lavage and plasma (P < 0.05). Neutrophils accumulated in bronchoalveolar lavage after APT, and atorvastatin pretreatment combined with sildenafil (but not atorvastatin alone) attenuated this effect (P < 0.05). APT increased lung lipid peroxidation and total protein concentrations in bronchoalveolar lavage, thus indicating oxidative stress and alveolar-capillary barrier damage, respectively. Both increases were attenuated by atorvastatin pretreatment alone or combined with sildenafil (P < 0.05). We conclude that pretreatment with atorvastatin protects against the pulmonary hypertension associated with APT and that sildenafil improves this response. These findings may reflect antioxidant effects and inhibited neutrophils/MMPs activation.


Asunto(s)
Hemodinámica/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Piperazinas/farmacología , Embolia Pulmonar/fisiopatología , Pirroles/farmacología , Sulfonas/farmacología , Enfermedad Aguda , Animales , Atorvastatina , Lavado Broncoalveolar , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Ventrículos Cardíacos/patología , Peroxidación de Lípido/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Metaloproteinasas de la Matriz/sangre , Metaloproteinasas de la Matriz/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Embolia Pulmonar/sangre , Embolia Pulmonar/inmunología , Embolia Pulmonar/metabolismo , Purinas/farmacología , Citrato de Sildenafil
19.
Crit Care Med ; 39(2): 349-56, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20890187

RESUMEN

OBJECTIVES: Up-regulated matrix metalloproteinases may be involved in the development of cardiomyocyte injury and the degradation of troponin associated with acute pulmonary thromboembolism. We examined whether pretreatment with doxycycline (a nonspecific matrix metalloproteinase inhibitor) protects against cardiomyocyte injury associated with acute pulmonary thromboembolism. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Mongrel dogs. INTERVENTIONS: Anesthetized animals received doxycycline (10 mg/kg intravenously) or saline and acute pulmonary thromboembolism was induced with autologous blood clots injected into the right atrium. Control animals received doxycycline (or saline). MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements were performed, and acute pulmonary thromboembolism increased baseline mean pulmonary arterial pressure and pulmonary vascular resistance by approximately 160% and 362%, respectively (both p < .05), 120 mins after acute pulmonary thromboembolism. Pretreatment with doxycycline attenuated these increases (to 125% and 232%, respectively; both p < .05). Although acute pulmonary thromboembolism tended to increase the right ventricle maximum rate of isovolumic pressure development and the maximum rate of isovolumic pressure decay, doxycycline produced no effects on these parameters. Gelatin zymograms of right ventricle showed that acute pulmonary thromboembolism marginally increased matrix metalloproteinase-9 (but not matrix metalloproteinase-2) levels in the right ventricle. A fluorometric assay to assess net matrix metalloproteinase activities showed that acute pulmonary thromboembolism increased matrix metalloproteinase activities in the right ventricle by >100% (p < .05), and this finding was confirmed by in situ zymography of the right ventricle. Doxycycline attenuated acute pulmonary thromboembolism-induced increases in right ventricle matrix metalloproteinase activities. Acute pulmonary thromboembolism induced neutrophil accumulation in the right ventricle, as estimated by myeloperoxidase activity, and doxycycline blunted this effect (p < .05). Serum cardiac troponin I concentrations, which reflect cardiomyocyte injury, increased after acute pulmonary thromboembolism, and this increase was attenuated by pretreatment with doxycycline (p < .05). CONCLUSIONS: We found evidence supporting the idea that acute pulmonary thromboembolism is associated with increased matrix metalloproteinase activities in the right ventricle, which may lead to degradation of sarcomeric proteins, including cardiac troponin I. Inhibition of matrix metalloproteinases may be an effective therapeutic intervention in the management of acute pulmonary thromboembolism.


Asunto(s)
Doxiciclina/administración & dosificación , Inhibidores de la Metaloproteinasa de la Matriz , Miocitos Cardíacos/efectos de los fármacos , Embolia Pulmonar/tratamiento farmacológico , Disfunción Ventricular Derecha/prevención & control , Enfermedad Aguda , Análisis de Varianza , Animales , Gasto Cardíaco , Modelos Animales de Enfermedad , Perros , Femenino , Hemodinámica/fisiología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Distribución Aleatoria , Valores de Referencia , Estadísticas no Paramétricas , Troponina I/sangre , Disfunción Ventricular Derecha/patología
20.
Nitric Oxide ; 23(4): 284-8, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-20804854

RESUMEN

While endogenous nitric oxide (NO) may be relevant to the beneficial hemodynamic effects produced by sildenafil during acute pulmonary embolism (APE), huge amounts of inducible NO synthase (iNOS)-derived NO may contribute to lung injury. We hypothesized that iNOS inhibition with S-methylisothiourea could attenuate APE-induced increases in oxidative stress and pulmonary hypertension and, therefore, could improve the beneficial hemodynamic and antioxidant effects produced by sildenafil during APE. Hemodynamic evaluations were performed in non-embolized dogs treated with saline (n=4), S-methylisothiourea (0.01 mg/kg followed by 0.5 mg/kg/h, n=4), sildenafil (0.3 mg/kg, n=4), or S-methylisothiourea followed by sildenafil (n=4), and in dogs that received the same drugs and were embolized with silicon microspheres (n=8 for each group). Plasma nitrite/nitrate (NOx) and thiobarbituric acid reactive substances (TBARS) concentrations were determined by Griess and a fluorometric assay, respectively. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 25±1.7 mm Hg and by 941±34 dyn s cm(-5) m(-2), respectively. S-methylisothiourea neither attenuated APE-induced pulmonary hypertension, nor enhanced the beneficial hemodynamic effects produced by sildenafil after APE (>50% reduction in pulmonary vascular resistance). While sildenafil produced no change in plasma NOx concentrations, S-methylisothiourea alone or combined with sildenafil blunted APE-induced increases in NOx concentrations. Both drugs, either alone or combined, produced antioxidant effects. In conclusion, although iNOS-derived NO may play a key role in APE-induced oxidative stress, our results suggest that the iNOS inhibitor S-methylisothiourea neither attenuates APE-induced pulmonary hypertension, nor enhances the beneficial hemodynamic effects produced by sildenafil.


Asunto(s)
Hemodinámica/efectos de los fármacos , Isotiuronio/análogos & derivados , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piperazinas/farmacología , Embolia Pulmonar/metabolismo , Sulfonas/farmacología , Enfermedad Aguda , Animales , Perros , Femenino , Isotiuronio/farmacología , Masculino , Nitratos/sangre , Óxido Nítrico/análisis , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/sangre , Estrés Oxidativo , Purinas/farmacología , Citrato de Sildenafil , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis
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