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Long-term ß-adrenoceptor (ß-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether ß-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the ß-AR agonist isoproterenol (Iso; 1â µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to ß-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with ß3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11ß-HSD1 protein expression. These results show that ß3-AR signaling leads to upregulation of 11ß-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Corticosterona , Isoproterenol , Animales , Masculino , Ratas , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Tejido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Corticosterona/metabolismo , Medios de Cultivo Condicionados/farmacología , Isoproterenol/farmacología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptores Adrenérgicos beta/metabolismoRESUMEN
Isoproterenol administration is associated with cardiac inflammation and decreased NO availability. Melatonin has been reported to have cardioprotective effect. The aim of this study was to investigate the effect of melatonin on NO bioavailability and inflammation in myocardial injury induced by isoproterenol. Isoproterenol was administrated in male Wistar rats for 7 days to induce cardiac injury. The animals were divided into 3 groups: Control, Isoproterenol, Isoproterenol + Melatonin. Animals received melatonin for 7 days. Echocardiographic analysis was performed and the hearts were collected for molecular analysis. Animals that received isoproterenol demonstrated a reduction in left ventricle systolic and diastolic diameter, indicating the presence of concentric hypertrophy. Melatonin was able to attenuate this alteration. Melatonin also improved NO bioavailability and decreased NF-κß, TNFα and IL-1ß expression. In conclusion, melatonin exhibited a cardioprotective effect which was associated with improving NO bioavailability and decreasing the pro-inflammatory proteins.
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Disponibilidad Biológica , Isoproterenol , Melatonina , Óxido Nítrico , Ratas Wistar , Animales , Melatonina/farmacología , Óxido Nítrico/metabolismo , Masculino , Ratas , Cardiotónicos/farmacología , Miocardio/metabolismo , Miocardio/patología , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Lesiones Cardíacas/metabolismo , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/patologíaRESUMEN
SUMMARY: The main cause of mortality and disability globally is myocardial infarction (MI). Isoproterenol (ISO), a β-adrenoceptor agonist, has been used to induce rat myocardial necrosis. Whereas interleukin-37 (IL-37) has anti-inflammatory and cytoprotective properties. The study aimed to investigate the potential protective effects of IL-37 administration on cardiac architecture, oxidative stress, and inflammatory markers during ISO-induced MI in rats. Three groups of adult male rats were used in this study, the normal control group (n=8), ISO-induced MI group (n=8) that received isoproterenol hydrochloride (ISO) (100 mg/kg/day, SC, for the first 2 consecutive days), and IL-37-treated group (ISO+IL-37) (n=8) that received recombinant human IL-37 (40 µg/kg /day, intraperitoneally, for 2 weeks during and after ISO injections. Heart rate (HR.) and ECG changes were monitored. Some oxidative stress markers such as superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) tissue levels in the tissue homogenate were assayed. Interleukin- 6 (IL-6), tumor necrosis factor- α (TNF-α), caspase-8, P53, and C- reactive protein (CRP) were among the inflammatory markers examined. In addition, serum levels of creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) were analyzed to evaluate the myocardial injury. For histological analysis, tissues were sectioned, fixed in paraffin, and stained with hematoxylin and eosin (H&E), Masson Trichrome and, immunohistochemical against NF-kB, TNF-α, and Caspase-9. IL-37 improved ECG changes, cardiac enzyme markers, and some inflammatory markers of oxidative stress in ISO-induced MI. It also improved the histopathological and immunohistochemical changes in MI. In conclusion: IL-37 might be a promising therapeutic modality in myocardial infarction.
La principal causa de mortalidad y discapacidad a nivel mundial es el infarto de miocardio (IM). El isoproterenol (ISO), un agonista de los receptores adrenérgicos β, se ha utilizado para inducir necrosis miocárdica en ratas. Mientras que la interleucina-37 (IL-37) tiene propiedades antiinflamatorias y citoprotectoras. El estudio tuvo como objetivo investigar los posibles efectos protectores de la administración de IL-37 en la arquitectura cardíaca, el estrés oxidativo y los marcadores inflamatorios durante el infarto de miocardio inducido por ISO en ratas. En este estudio se utilizaron tres grupos de ratas macho adultas, el grupo control normal (n=8), el grupo con IM inducido por ISO (n=8) que recibió clorhidrato de isoproterenol (ISO) (100 mg/kg/día, SC, durante los primeros 2 días consecutivos) y el grupo tratado con IL-37 (ISO+IL- 37) (n=8) que recibió IL-37 humana recombinante (40 µg/kg/día, por vía intraperitoneal, durante 2 semanas durante y después de las inyecciones de ISO. Se monitorearon la frecuencia cardíaca (FC) y los cambios en el ECG. Se analizaron algunos marcadores de estrés oxidativo como la superóxido dismutasa (SOD), el óxido nítrico (NOx), el malondialdehído (MDA) y los niveles tisulares de glutatión (GSH) en el homogeneizado de tejido. La interleucina-6 (IL-6), el factor de necrosis tumoral-α (TNF-α), la caspasa-8, la P53 y la proteína C reactiva (CRP) se encontraban entre los marcadores inflamatorios examinados. Se analizaron los niveles de creatinoquinasa (CK-MB) y lactato deshidrogenasa (LDH) para evaluar la lesión miocárdica; para el análisis histológico se seccionaron los tejidos, se fijaron en parafina y se tiñeron con hematoxilina y eosina (H&E), Tricromo de Masson e inmunohistoquímica contra NF-kB, TNF-α y Caspasa-9. IL-37 mejoró los cambios de ECG, los marcadores de enzimas cardíacas y algunos marcadores inflamatorios de estrés oxidativo en el IM inducido por ISO. Además mejoró los cambios histopatológicos e inmunohistoquímicos en MI. En conclusión: la IL-37 podría ser una modalidad terapéutica prometedora en el infarto de miocardio.
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Animales , Masculino , Ratas , Interleucinas/administración & dosificación , Corazón/efectos de los fármacos , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/prevención & control , Inmunohistoquímica , Ratas Wistar , Estrés Oxidativo/efectos de los fármacos , Inflamación , Isoproterenol/efectos adversosRESUMEN
Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E'-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress.
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Cardiomiopatías , Remodelación Ventricular , Ratones , Masculino , Animales , Isoproterenol/efectos adversos , Isoproterenol/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Ratones Noqueados , Cardiomiopatías/inducido químicamente , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/genética , Fibrosis , Miocitos Cardíacos/metabolismo , Ratones Endogámicos C57BLRESUMEN
SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.
RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.
Asunto(s)
Animales , Masculino , Ratas , Canagliflozina/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Ratas Wistar , NG-Nitroarginina Metil ÉsterRESUMEN
Chagas disease principally affects Latin-American people, but it currently has worldwide distribution due to migration. Death among those with Chagas disease can occur suddenly and without warning, even in those who may not have evidence of clinical or structural cardiac disease and who are younger than 60 years old. HCN4 channels, one of the principal elements responsible for pacemaker currents, are associated with cardiac fetal reprogramming and supraventricular and ventricular arrhythmias, but their role in chagasic arrhythmias is not clear. We found that a single-dose administration of ivabradine, which blocks HCN4, caused QTc and QRS enlargement and an increase in P-wave amplitude and was associated with ventricular and supraventricular arrhythmias in mice challenged with isoproterenol, a chronotropic/ionotropic positive agent. Continuous treatment with ivabradine did not alter the QTc interval, but P-wave morphology was deeply modified, generating supraventricular arrhythmias. In addition, we found that repolarization parameters improved with ivabradine treatment. These effects could have been caused by the high HCN4 expression observed in auricular and ventricular tissue in infected mice. Thus, we suggest, for the first time, that molecular remodeling by overexpression of HCN4 channels may be related to supraventricular arrhythmias in acute Chagas disease, causing ivabradine over-response. Thus, ivabradine treatment should be administered with caution, while HCN4 overexpression may be an indicator of heart failure and/or sudden death risk.
RESUMEN
We have developed and characterized a model of isoproterenol (ISO)-induced myocardial necrosis, identifying three stages of cardiac damage: a pre-infarction (0-12 h), infarction (24 h), and post-infarction period (48-96 h). Using this model, we have previously found alterations in calcium homeostasis and their relationship with oxidant stress in mitochondria, which showed deficient oxygen consumption and coupled ATP synthesis. Therefore, the present study was aimed at assessing the mitochondrial ability to transport and oxidize cytoplasmic reducing equivalents (NADH), correlating the kinetic parameters of the malate-aspartate shuttle, oxidant stress, and mitochondrial functionality. Our results showed only discreet effects during the cardiotoxic ISO action on the endogenous malate-aspartate shuttle activity, suggesting that endogenous mitochondrial NADH oxidation capacity (Nohl dehydrogenase) was not affected by the cellular stress. On the contrary, the reconstituted system showed significant enhancement in maximal capacity of the malate-aspartate shuttle activity only at later times (post-infarction period), probably as a compensatory part of cardiomyocytes' response to the metabolic and functional consequences of the infarcted tissue. Therefore, these findings support the notion that heart damage associated with myocardial infarction suffers a set of sequential biochemical and metabolic modifications within cardiomyocytes, where mitochondrial activity, controlling the redox state, could play a relevant role.
RESUMEN
PURPOSE: Although the pathophysiological response of cardiac tissue to pro-hypertrophic stimulus is well characterized, a comprehensive characterization of the molecular events underlying the pathological hypertrophy in cardiomyocytes during the early compensated cardiac hypertrophy is currently lacking. EXPERIMENTAL DESIGN: A quantitative label-free proteomic analysis of cardiomyocytes isolated was conducted from mice treated subcutaneously with isoproterenol (ISO) during 7 days in comparison with cardiomyocytes from control animals (CT). RESULTS: Canonical pathway analysis of dysregulated proteins indicated that ISO-hypertrophy drives the activation of actin cytoskeleton and integrin-linked kinase (ILK) signaling, and inhibition of the sirtuin signaling. Alteration in cardiac contractile function and calcium signaling are predicted as downstream effects of ISO-hypertrophy probably due to the upregulation of key elements such as myosin-7 (MYH7). Confocal microscopy corroborated that indeed ISO-treatment led to increased abundance of MYH7. Potential early markers for cardiac hypertrophy as APBB1, GOLGA4, HOOK1, KATNA1, KIFBP, MAN2B2, and SLC16A1 are also reported. CONCLUSIONS AND CLINICAL RELEVANCE: The data consist in a complete molecular mapping of ISO-induced compensated cardiac hypertrophy model at cardiomyocyte level. Marker candidates reported may assist early diagnosis of cardiac hypertrophy and ultimately heart failure.
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Cardiomegalia/metabolismo , Isoproterenol/toxicidad , Miocitos Cardíacos/metabolismo , Proteoma/genética , Transducción de Señal , Actinas/genética , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/fisiopatología , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Cadenas Pesadas de Miosina/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ProteómicaRESUMEN
Stress-induced cardiomyopathy (SIC) results from a profound catecholaminergic surge during strong emotional or physical stress. SIC is characterized by acute left ventricular apex hypokinesia, in the absence of coronary arteries occlusion, and can lead to arrhythmias and acute heart failure. Although, most SIC patients recover, the process could be slow, and recurrence or death may occur. Despite that the SIC common denominator is a large catecholamine discharge, the pathophysiological mechanism is incompletely understood. It is thought that catecholamines have direct cytotoxicity on apical ventricular myocytes (VM), which have the highest ß-adrenergic receptors density, and whose overstimulation might cause acute Ca2+ overload and oxidative stress, causing death in some VM and stunning others. Rodents receiving acute isoproterenol (ISO) overdose (OV) mimic SIC development, however, they have not been used to simultaneously assess Ca2+ handling and contractility status in isolated VM, which might explain ventricular hypokinesia. Therefore, treating rats with a single ISO-OV (67â¯mg/kg body weight), we sought out to characterize, with confocal imaging, Ca2+ and shortening dynamics in Fluo-4-loaded VM, during the early (1-5 days) and late post-acute phases (15 days). We found that ISO-OV VM showed contractile dysfunction; blunted shortening with slower force development and relaxation. These correlated with Ca2+ mishandling; blunted Ca2+ transient, with slower time to peak and SR Ca2+ recovery. SR Ca2+ content was low, nevertheless, diastolic Ca2+ sparks were more frequent, and their duration increased. Contractility and Ca2+ dysfunction aggravated or remained altered over time, explaining slow recovery. We conclude that diminished VM contractility is the main determinant of ISO-OV hypokinesia and is mostly related to Ca2+ mishandling.
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Señalización del Calcio , Cardiomiopatías/fisiopatología , Separación Celular , Ventrículos Cardíacos/patología , Contracción Miocárdica , Miocitos Cardíacos/patología , Animales , Calcio/metabolismo , Cardiomiopatías/metabolismo , Citosol/metabolismo , Diástole , Modelos Animales de Enfermedad , Sobredosis de Droga , Ventrículos Cardíacos/fisiopatología , Isoproterenol , Masculino , Miocitos Cardíacos/metabolismo , Ratas Wistar , Retículo Sarcoplasmático/metabolismo , Sístole , Factores de TiempoRESUMEN
Cardiovascular diseases are the main source of death and morbidity in developed and developing nations. Animal models are required to propel our understanding of the pathogenesis, increase our knowledge, disease progress, and mechanism behind cardiovascular disorder, providing new approaches focused to improve the diagnostic and the treatment of these pathological conditions and additionally to test various therapeutic ways to deal with tissue regeneration and re-establish heart working following damage. A perfect model framework ought to be reasonable, effectively controlled, reproducible, and physiologically illustrative of human disease, show cardinal signs and pathology that resembles after the human ailment and ethically stable. The decision of selection of animal model should be considered precisely since it influences exploratory results and whether results of the research can be sensibly matched with the human. In this way, no specific technique splendidly reproduces the human disease, and relying upon the model, extra cost burden, resources, infrastructure and the necessity for technical hands, should also be kept under consideration. Here we have discussed and compiled various methods of inducing myocardial infarction in animals, basically by surgery, chemicals and through genetic modification, this may benefit the researchers in getting a complied data regarding various methods through which they can induce myocardial infarction in animals.
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ß-Adrenergic signaling regulates many physiological processes in skeletal muscles. A wealth of evidence has shown that ß-agonists can increase skeletal muscle mass in vertebrates. Nevertheless, to date, the specific role of ß-adrenergic receptors in different cell phenotypes (myoblasts, fibroblasts, and myotubes) and during the different steps of embryonic skeletal muscle differentiation has not been studied. Therefore, here we address this question through the analysis of embryonic chick primary cultures of skeletal muscle cells during the formation of multinucleated myotubes. We used isoproterenol (ISO), a ß-adrenergic receptor agonist, to activate the ß-adrenergic signaling and quantified several aspects of muscle differentiation. ISO induced an increase in myoblast proliferation, in the percentage of Pax7-positive myoblasts and in the size of skeletal muscle fibers, suggesting that ISO activates a hyperplasic and hypertrophic muscle response. Interestingly, treatment with ISO did not alter the number of fibroblast cells, suggesting that ISO effects are specific to muscle cells in the case of chick myogenic cell culture. We also show that rapamycin, an inhibitor of the mammalian target of rapamycin signaling pathway, did not prevent the effects of ISO on chick muscle fiber size. The collection of these results provides new insights into the role of ß-adrenergic signaling during skeletal muscle proliferation and differentiation and specifically in the regulation of skeletal muscle hyperplasia and hypertrophy.
RESUMEN
ETHNOPHARMACOLOGY RELEVANCE: The leaves of Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, the cardioprotective effect of this plant has not been studied yet. AIM OF THIS STUDY: To evaluate the cardioprotective effects of the hydroalcoholic extract of the leaves of Alpinia zerumbet (AZE) against isoproterenol (ISO)-induced myocardial infarction in rats. MATERIAL AND METHODS: Rats were pretreated orally with AZE (300â¯mg/kg) for 30 days prior to ISO-induced myocardial infarction. The rats were sacrificed and hearts were collected and homogenized for biochemical analysis. At the end of the experiment, cardiac marker enzyme levels, histological and morphometric parameters, and hemodynamic measurements were assessed. Phytochemical compounds were verified by gas chromatography-mass spectrometry (GC-MS). RESULTS: Rats administered with ISO showed a significant increase in cardiac marker enzymes, i.e., in creatine kinase-NAC (CK-NAC) and CK-MB. Triphenyltetrazolium chloride (TTC) staining exhibited an increase in infarct areas. In the animals treated with ISO induced a significant increase in heart rate. Pretreatment with AZE significantly inhibited these effects of ISO. Moreover, biochemical findings were supported by histopathological observations. The GC-MS analyses of AZE identified volatile oils, kavalactones, and phytosterols. CONCLUSIONS: Haemodynamic, biochemical alteration and histopathological results suggest a cardioprotective protective effect of oral administration of AZE in isoproterenol induced cardiotoxicity.
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Alpinia , Cardiotónicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Creatina Quinasa/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Isoproterenol , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Hojas de la Planta , Ratas WistarRESUMEN
Chronic stimulation of the ß-adrenergic sympathetic system induces vascular dysfunction which is associated with increased inflammatory cytokines production. A recently proposed therapy to control vascular injury through inflammatory processes involves inhibition of the enzyme dipeptidyl peptidase-IV (DPP4). The present study investigates whether the inhibition of DPP4 prevents the increase in inflammatory markers induced by isoproterenol and restores endothelial function in vivo and in vitro. Male Wistar rats were divided into four groups: vehicle (VHC), an isoproterenol-treated group (ISO), a sitagliptin-treated group (SITA), and an isoproterenol and sitagliptin-treated group (ISO + SITA). The ISO group exhibited significantly increased contractile responses to phenylephrine associated with reduced endothelial participation, which was totally prevented by DPP4 inhibition. In vitro incubation with isoproterenol had no effect on vascular smooth muscle cells, however isoproterenol increased the activity of DPP4 and the expression of inflammatory cytokines in endothelial cells, while sitagliptin reduced the level of cytokines to basal level. In conclusion, we have shown that beta-adrenergic receptor activation can increase DPP4 activity, which was associated with vascular dysfunction and cytokine expression in endothelial cells. The important role of DPP4 was further supported by sitagliptin, which reversed vascular changes induced by isoproterenol in vivo and in vitro.
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Agonistas Adrenérgicos beta/toxicidad , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Isoproterenol/toxicidad , Fosfato de Sitagliptina/farmacología , Animales , Citocinas/metabolismo , Dipeptidil Peptidasa 4/efectos de los fármacos , Dipeptidil Peptidasa 4/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipoglucemiantes/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Fenilefrina/farmacología , Ratas , Ratas WistarRESUMEN
Guinep is traditionally used in the management of cardiovascular ailments. This study aims to evaluate its medicinal constituents and effects in the management of myocardial injury in an experimental isoproterenol (ISO) rat model. Sprague-Dawley rats were randomly assigned to four groups: Group 1 was the control group; Group 2 received M. bijugatus extract (100 mg/Kg; MB) for six weeks; Group 3 was given ISO (85 mg/Kg) i.p. twice during a 24-hour period; and Group 4 was given ISO (85 mg/Kg) i.p. and MB extract (100 mg/Kg) for six weeks. The MB was administered orally by gavage, daily. The blood pressure of conscious animals was measured, while ECG was performed under anesthesia. Blood and serum were collected for biochemical and hematological analysis. The ISO group treated with MB showed a significant decrease (p < 0.001) in (SBP), diastolic (DBP), mean arterial (MAP) and heart rate (HR) compared to the ISO only group. Conversely, MB treated rats that were not induced with ISO displayed a significant decreases (p < 0.001) in SBP, DBP, MAP, and HR. ISO significantly elevated the ST segment (p < 0.001) and shortened the QTc interval (p < 0.05), which were recovered after treatment with 100 mg/Kg of MB. In addition, the results showed a significant decrease (p < 0.001) in the heart to body weight ratio of the ISO group treated with MB compared to the ISO only group. Furthermore, the extract normalized the hematological values depressed by the ISO while significantly elevating the platelet count. UHPLC high-resolution orbitrap mass spectrometry analysis results revealed the presence of several antioxidants like vitamin C and related compounds, phenolic acids, flavonoid, fatty acids (oxylipins), and terpene derivatives. The results of this study indicated that Melicoccus bijugatus did display some cardio-protective effects in relation to myocardial injury.
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Lesiones Cardíacas/prevención & control , Isoproterenol/efectos adversos , Magnoliopsida/química , Metabolómica/métodos , Extractos Vegetales/administración & dosificación , Administración Oral , Animales , Determinación de la Presión Sanguínea , Cromatografía Líquida de Alta Presión , Electrocardiografía , Frutas , Jugos de Frutas y Vegetales/análisis , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Espectrometría de Masas , Ratones , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
GABA transporters regulate synaptic GABA levels and dysfunctions in this system might result in psychiatric disorders. The endocannabinoid system (ECS) is the main circuit breaker in the nervous system and may alter noradrenaline (NA) communication, which in turn modulates the release of GABA. However, a close relationship between these systems has not been recognized. We asked whether NA and ECS might control extracellular GABA levels in slices of frontal cortex (FC) of adolescent Swiss mice with 40 days after birth (PN40). Here we show that NA and isoproterenol (ISO), a beta-adrenergic agonist, increased [3H]-GABA uptake in mice FC, while alpha1-adrenergic agonist phenylephrine had no effect. As GAT-1 is expressed and fully functional at the FC, addition of NO-711, a GAT-1 inhibitor, dose dependently blocked [3H]-GABA uptake. The increase of [3H]-GABA uptake induced by ISO was also blocked by NO-711. [3H]-GABA release induced by 80â¯mM KCl was reduced by NO-711, but not by removal of Ca2+. ISO also increased cyclic AMP (cAMP) levels and addition of WIN 55,212-2, a mixed CB1/CB2 receptor agonist, inhibited the effect of ISO in GABA uptake increase, GAT-1 expression and cAMP levels compared to control. Our data show that GABA transport increased by NA and ISO is negatively regulated by cannabinoid receptor agonist WIN55,212-2.
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Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Lóbulo Frontal/efectos de los fármacos , Proteínas Transportadoras de GABA en la Membrana Plasmática/efectos de los fármacos , Morfolinas/farmacología , Naftalenos/farmacología , Animales , Endocannabinoides/metabolismo , Lóbulo Frontal/metabolismo , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Ratones , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/efectos de los fármacosRESUMEN
Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca2+]i) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca2+]i and contractility. We tested the hypothesis that in the aged heart, [Ca2+]i handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20â»24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca2+]i, isolated cardiac myocytes were field-stimulated and [Ca2+]i was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts (p < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca2+]i in aged myocytes (p < 0.05). Time-50 [Ca2+]i decay was increased in aged myocytes (p < 0.05) and reduced towards normal by NOX inhibition. In addition, we found that myofilaments Ca2+ sensitivity was reduced in aged myocytes (p < 0.05), and was further reduced by apocynin. NOX2 expression along with NADPH oxidase activity was increased in aged hearts. Phospholamban phosphorylation (Ser16/Thr17) after isoproterenol treatment was reduced in aged hearts compared to adults and was restored by apocynin treatment (p < 0.05). In conclusion, ß-adrenergic-induced contractility was depressed in aged hearts, and NOX inhibition restored back to normal. Moreover, altered Ca2+ handling in aged myocytes was also improved by NOX inhibition. These results suggest a NOX-dependent effect in aged myocytes at the level of Ca2+ handling proteins and myofilaments.
Asunto(s)
Acetofenonas/farmacología , Agonistas Adrenérgicos beta/farmacología , Benzoxazoles/farmacología , Calcio/metabolismo , Corazón/efectos de los fármacos , Isoproterenol/farmacología , Contracción Miocárdica/efectos de los fármacos , NADPH Oxidasas/antagonistas & inhibidores , Triazoles/farmacología , Envejecimiento/efectos de los fármacos , Animales , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Femenino , Corazón/fisiología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , NADPH Oxidasas/metabolismo , RatasRESUMEN
Different human-like cardiomyopathies associated to ß-adrenergic stimulation are experimentally modeled in animals through variations in dose, route, and duration of administration of different cardiotoxic drugs. However, associated changes in the vasculature and their relation to systemic inflammation, and the influence of cardiovascular diseases risk factors (gender and age) upon them are seldom analyzed. Here we studied the effect of age and gender on the vasoreactivity of aortas from mice subjected to in vivo repeated ß-adrenergic stimulation with different doses of isoproterenol (ISO) in association with circulating inflammatory cytokines. Young (2 months) and old (18 months) male and female mice received 0 (control), 5, 40, 80 or 160 µg/g/d of ISO (7 days, s.c.). IL-1α, IL-4 and vascular cell adhesion molecule-1 (VCAM-1) were quantified in plasma. In vitro, norepinephrine-induced vasoconstriction and acetylcholine-induced relaxation were measured in aortas. No differences in contraction, relaxation, IL-1α, and IL-4 were found between control young males and females. Age decreased contraction in males and relaxation was lower in females and abolished in males. VCAM-1 was higher in young males than in females and increased in old mice. Vasoconstriction in ISO-treated mice results as a bell-shaped curve on contraction in young and old males, with lower values in the latter. In females, ISO-160 increased contraction in young females but decreased it in old females. Vasorelaxation was reduced in ISO-treated young males and females. ISO-80 and 160 reduced vasorelaxation in old females, and intermediate doses relaxed aortas from old males. VCAM-1 was higher in young and old males with ISO-80 and 160; while VCAM-1 was higher only with ISO-160 in old females. Our results demonstrate that repeated ß-adrenergic stimulation modifies vascular reactivity depending on gender, age, and dose. Females were less sensitive to alterations in vasoreactivity, and young females required a higher amount of the adrenergic stimuli than old females to show vascular alterations. Changes were independent of IL-1α and IL-4. VCAM-1 only changed in old females stimulated with ISO 160. Our results highlight the relevance of considering and comparing in the same study females and aged organisms to improve the accuracy of applications to clinical studies.
RESUMEN
Abstract A case of intraoperative awareness during ablation of pulmonary veins-one of the most widely used techniques in interventional cardiology-is discussed. An infusion of isoproterenol was administered following the ablation of ectopic foci. A few seconds after the infusion the patient experienced increased heart rate and intraoperative awareness manifested as an abrupt patient movement and bispectral index elevation. This has been described in similar procedures, following the administration of isoproterenol. In our opinion, the isoproterenol infusion caused the increased heart rate and subsequent abrupt rise in cardiac output. As an inversely proportional relationship between the propofol concentrations and cardiac output has been described, we believe that this rise in cardiac output could have favored the decline in the concentrations of propofol, leading to an intraoperative awareness episode.
Resumen Presentamos un caso de despertar intraoperatorio durante la ablación de venas pulmonares, una de las técnicas más empleadas por los cardiólogos intervencionistas. Tras la ablación de focos ectópicos se procede a la infusión de isoproterenol. Segundos después de la infusión se produce un aumento de la frecuencia cardíaca seguido de un despertar intraoperatorio traducido como un movimiento brusco del paciente y un aumento en el índice bi-espectral (BIS). Esto ha sido descrito en procedimientos similares tras la administración de isoproterenol. En nuestra opinión, la infusión de isoproterenol provocó un aumento de la frecuencia cardiaca y secundariamente del gasto cardíaco de forma brusca. Dado que se ha descrito una relación inversamente propocional entre las concentraciones de propofol y el gasto cardíaco, pensamos que este aumento del gasto cardíaco pudo condicionar un descenso de las concentraciones de propofol y esto causar el episodio de despertar intraoperatorio.
Asunto(s)
Humanos , Persona de Mediana Edad , Venas Pulmonares , Gasto Cardíaco , Propofol , Ablación por Catéter , Despertar Intraoperatorio , Isoproterenol , Anestésicos , Cardiología , Ruscus , Cardiólogos , Frecuencia CardíacaRESUMEN
BACKGROUND/AIMS: To assess the possible contribution of the ß-adrenergic overstimulation in early stages of renal injury, the present study evaluated, in rats, the effects of the ß-adrenoceptor agonist isoproterenol (ISO) on renal function and morphology, as well as the renal mRNA and protein expression of the NADPH oxidase isoform 4 (Nox 4) and subunit p22phox, endoplasmic reticulum (ER) stress, pro-inflammatory, pro-apoptotic and renin-angiotensin system (RAS) components. METHODS: Wistar rats received ISO (0.3 mg.kg-1.day-1 s.c.) or vehicle (control) for eight days. At the end of the treatment, food and water intake, urine output and body weight gain were evaluated and renal function studies were performed. Renal tissue was used for the morphological, quantitative PCR and immunohistochemical studies. RESULTS: ISO did not change metabolic parameters or urine output. However it induced a decrease in renal blood flow and an increase in the filtration fraction. These changes were accompanied by increased cortical mRNA and protein expression for the renal oxidative stress components including Nox 4 and p22phox; ER stress, pro-inflamatory, pro-apoptotic as well as RAS components. ISO also induced a significant increase in medullar renin protein expression. CONCLUSION: These findings support relevant information regarding the contribution of specific ß-adrenergic hyperactivity in early stage of renal injury, indicating the reactive oxygen species, ER stress and intrarenal RAS as important factors in this process.