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OBJECTIVES: This study aimed to evaluate the intensity of the subacute local biological effects after implantation and osseoconductive potential of novel hydroxyapatite-based bone substitute coated with poly (lactide-co-glycolide), named ALBO-OS, in comparison to Bio-Oss®. METHODS: Fifteen male Wistar rats, randomly assigned into groups: 10, 20, and 30 days (nê5), were subcutaneously implanted with ALBO-OS and Bio-Oss®. Furthermore, artificially made bone defects on both rat's tibias were implanted with experimental materials. Unimplanted defects represented negative control. After the animals' euthanizing, tissue samples were prepared and analyzed histologically and histomorphometrically. RESULTS: Normal healing of the epithelial tissue was observed, with no signs of infection or necrosis. Minimal vascular congestion was noted immediately around the graft, with no signs of tissue oedema, with a minimal capsule thickness. The applied material did not cause an inflammatory response (IR) of significant intensity, and 20 days after implantation, the IR was mainly assessed as minimal. The tibial specimen showed that ALBO-OS has good osseoconductive potential, similar to Bio-Oss®, as well as low levels of acute and subacute inflammation. CONCLUSIONS: The tested material exhibits satisfying biocompatibility, similar to Bio-Oss®.
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Chronic hypertensive pregnancy (CHP) is a growing health issue with unknown etiology. Vasopressin (VP), a nonapeptide synthesized in paraventricular (PVN) and supraoptic nucleus (SON), is a well-known neuroendocrine and autonomic modulator of the cardiovascular system, related to hypertension development. We quantified gene expression of VP and its receptors, V1aR and V1bR, within the PVN and SON in CHP and normal pregnancy, and assessed levels of secreted plasma VP. Also, we evaluated autonomic cardiovascular adaptations to CHP using spectral indices of blood pressure (BPV) and heart rate (HRV) short-term variability, and spontaneous baroreflex sensitivity (BRS). Experiments were performed in female spontaneously hypertensive rats (SHRs) and in normotensive Wistar rats (WRs). Animals were equipped with a radiotelemetry probe for continuous hemodynamic recordings before and during pregnancy. BPV, HRV and BRS were assessed using spectral analysis and the sequence method, respectively. Plasma VP was determined by ELISA whilst VP, V1aR, and V1bR gene expression was analyzed by real-time-quantitative PCR (RT-qPCR). The results show that non-pregnant SHRs exhibit greater VP, V1aR, and V1bR gene expression in both PVN and SON respectively, compared to Wistar dams. Pregnancy decreased VP gene expression in the SON of SHRs but increased it in the PVN and SON of WRs. Pregnant SHRs exhibited a marked drop in plasma VP concentration associated with BP normalization. This triggered marked tachycardia, heart rate variability increase, and BRS increase in pregnant SHRs. It follows that regardless of BP normalization in late pregnancy, SHRs exhibit cardiovascular vulnerability and compensate by recruiting vagal mechanisms. Pregnant SHR dams have reduced expression of VP in SON associated with increased V1bR expression, lower plasma VP, normal BP during late pregnancy and marked signs of enhanced sympathetic cardiac stimulation (increased HR and LFHR variability) and recruitment of vagal mechanisms (enhancement of BRS and HFHR variability).
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NEW FINDINGS: What is the central question of this study? Although the involvement of reactive oxidative species in triggering hypertension has been documented, there are no data about the role of antioxidant enzymes in the heart and aorta of borderline hypertensive rats kept in baseline conditions or exposed to high salt with or without repeated stress. What is the main finding and its importance? In borderline hypertensive rats, high salt intake and stress contribute significantly to increase blood pressure and antioxidative defence in the aorta but decrease it in the heart. Elucidating the early changes that accompany elevated blood pressure could provide new therapeutical venues for prevention and treatment of the condition. ABSTRACT: Hypertension and its complications are a leading cause of death in the human population. Several factors can contribute to development of hypertension, such as genetic predisposition, high salt intake and environmental stressors, underlying oxidative stress as one of its key trademarks. We studied the effects of increased salt intake and chronic stress on blood pressure parameters and the activity and protein levels of antioxidant enzymes in the heart and aorta of borderline hypertensive rats (BHRs) with genetic susceptibility to hypertension. All animals were randomized into four groups: (1) Wistar rats kept in baseline conditions; (2) BHRs kept in baseline conditions; (3) BHRs drinking 0.9% saline solution; and (4) BHRs drinking 0.9% saline solution and exposed to repeated heterotypic stress. The BHRs exhibited significantly higher blood pressure, mitochondrial superoxide dismutase (SOD2) and catalase (CAT) protein levels and lower glutathione peroxidase (GPx) and glutathione reductase (GR) activities in the aorta, followed by lower CAT and GPx protein levels and higher CAT and GR activities in the heart, compared with normotensive Wistar rats. In the BHR aorta, high salt intake elevated CAT and GPx activities, and when combined with stress it increased GPx and GR activities. In BHR hearts, high salt intake provoked lower CAT activity. Adding repeated stress to salt treatment further decreased CAT activity, in addition to Cu2+ -Zn2+ superoxide dismutase (SOD1) and GR activities. The protein level of CAT was lower, whereas SOD2 and GPx increased. Overall, our results suggest that BHR hearts are better adapted to oxidative pressure, compared with the aorta, when exposed to salt and stress.
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Antioxidantes , Hipertensión , Humanos , Ratas , Animales , Antioxidantes/metabolismo , Presión Sanguínea , Ratas Wistar , Cloruro de Sodio Dietético/farmacología , Solución Salina/farmacología , Catalasa/metabolismo , Estrés Oxidativo , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa/metabolismo , Aorta/metabolismoRESUMEN
INTRODUCTION: ST2 is the receptor for interleukin (IL)-33, the last discovered member of the IL-1 cytokine family. Acute inflammation is an early response of vascularized tissue to injury, in which alteration of micro- and macro-elements occurs. This study aimed to examine the alteration of cobalt, sodium, potassium, and calcium concentration at the site of acute inflammation and the role of ST2 in these alterations. MATERIAL AND METHODS: Wild-type (WT) and ST2 knockout (ST2-/-) mice were divided into groups: WT control group (WT-C), ST2 knockout control group (KO-C), WT inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). We induced acute inflammation by intramuscular injection of turpentine oil or saline in the case of the control group. After 12 h, we anesthetized mice and collected treated tissues for histopathological analysis and determination of cobalt, sodium, potassium, and calcium concentration by atomic absorption spectrometer. RESULTS: Histopathological analysis showed the inflammatory infiltrate and cell necrosis in the treated tissue in WT-I and KO-I. The concentration of sodium was significantly lower in WT-I than in WT-C. The concentration of potassium and cobalt was significantly lower in WT-I and KO-I when compared to WT-C and KO-C, respectively. However, the concentration of potassium and cobalt in the tissue was significantly lower in WT-I than in KO-I. The concentration of calcium in the tissue did not significantly differ between groups. CONCLUSION: We reported, to our knowledge for the first time, that ST2 is involved in decreasing sodium, potassium, and cobalt concentration at the site of acute inflammation.
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Calcio , Proteína 1 Similar al Receptor de Interleucina-1 , Animales , Ratones , Cobalto , Citocinas , Inflamación/inducido químicamente , Inflamación/patología , Interleucina-1 , Interleucina-33 , Ratones Noqueados , Potasio , Sodio , TrementinaRESUMEN
The paraventricular nucleus (PVN) is a highly organized structure of the hypothalamus that has a key role in regulating cardiovascular and osmotic homeostasis. Functionally, the PVN is divided into autonomic and neuroendocrine (neurosecretory) compartments, both equally important for maintaining blood pressure (BP) and body fluids in the physiological range. Neurosecretory magnocellular neurons (MCNs) of the PVN are the main source of the hormones vasopressin (VP), responsible for water conservation and hydromineral balance, and oxytocin (OT), involved in parturition and milk ejection during lactation. Further, neurosecretory parvocellular neurons (PCNs) take part in modulation of the hypothalamic-pituitary-adrenal axis and stress responses. Additionally, the PVN takes central place in autonomic adjustment of BP to environmental challenges and contributes to its variability (BPV), underpinning the PVN as an autonomic master controller of cardiovascular function. Autonomic PCNs of the PVN modulate sympathetic outflow toward heart, blood vessels and kidneys. These pre-autonomic neurons send projections to the vasomotor nucleus of rostral ventrolateral medulla and to intermediolateral column of the spinal cord, where postganglionic fibers toward target organs arise. Also, PVN PCNs synapse with NTS neurons which are the end-point of baroreceptor primary afferents, thus, enabling the PVN to modify the function of baroreflex. Neuroendocrine and autonomic parts of the PVN are segregated morphologically but they work in concert when the organism is exposed to environmental challenges via somatodendritically released VP and OT by MCNs. The purpose of this overview is to address both neuroendocrine and autonomic PVN roles in BP and BPV regulation.
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BACKGROUND: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. METHODS: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. RESULTS: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. CONCLUSIONS: We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.
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Cuerpo Carotídeo , Hipertensión , Animales , Presión Sanguínea , Cuerpo Carotídeo/metabolismo , Glucosa/metabolismo , Ratas , Ratas Endogámicas SHRRESUMEN
Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.
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Cardiomiopatías/prevención & control , Cardiotoxicidad/prevención & control , Doxorrubicina/toxicidad , Paroxetina/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/inducido químicamente , Cardiomiopatías/mortalidad , Cardiotónicos/farmacología , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.
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Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/clasificación , Cardiomiopatías/genética , Mapeo Cromosómico/métodos , Doxorrubicina/toxicidad , Animales , Cardiomiopatías/inducido químicamente , Masculino , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Approximate and sample entropies are acclaimed tools for quantifying the regularity and unpredictability of time series. This paper analyses the causes of their inconsistencies. It is shown that the major problem is a coarse quantization of matching probabilities, causing a large error between their estimated and true values. Error distribution is symmetric, so in sample entropy, where matching probabilities are directly summed, errors cancel each other. In approximate entropy, errors are accumulating, as sums involve logarithms of matching probabilities. Increasing the time series length increases the number of quantization levels, and errors in entropy disappear both in approximate and in sample entropies. The distribution of time series also affects the errors. If it is asymmetric, the matching probabilities are asymmetric as well, so the matching probability errors cease to be mutually canceled and cause a persistent entropy error. Despite the accepted opinion, the influence of self-matching is marginal as it just shifts the error distribution along the error axis by the matching probability quant. Artificial lengthening the time series by interpolation, on the other hand, induces large error as interpolated samples are statistically dependent and destroy the level of unpredictability that is inherent to the original signal.
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Previous studies showed contradictory results of static magnetic field (SMF) influence on behavior, hematological parameters and organ damage. The aim of this study was to investigate influence of subchronic continuous exposure to upward and downward oriented SMF of moderate intensity on behavior, hematological characteristics, heart and kidney tissue of spontaneously hypertensive rats. SH rats exposed to downward oriented SMF demonstrated lack of anxious-like behavior. SMF of either orientation caused decrease in the number of platelets in peripheral blood, granulocytes in the spleen and bone marrow and increase in the number of erythrocytes in the spleen, in both exposed groups. We also demonstrated that spontaneously hypertensive rats exposed to upward oriented SMF exhibited decreased lymphocytes count in blood, decreased bone marrow erythrocytes count and rats exposed to downward oriented SMF had increased lymphocytes count in bone marrow. The results showed adverse effect of differently oriented SMF on hematological parameters of spontaneously hypertensive rats. Also, exposure to different oriented SMF didn't affect their heart and kidney morphological characteristics.
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Hipertensión , Campos Magnéticos/efectos adversos , Animales , Ratas , Ratas Endogámicas SHR , BazoRESUMEN
The goal of this paper is to investigate the changes of entropy estimates when the amplitude distribution of the time series is equalized using the probability integral transformation. The data we analyzed were with known properties-pseudo-random signals with known distributions, mutually coupled using statistical or deterministic methods that include generators of statistically dependent distributions, linear and non-linear transforms, and deterministic chaos. The signal pairs were coupled using a correlation coefficient ranging from zero to one. The dependence of the signal samples is achieved by moving average filter and non-linear equations. The applied coupling methods are checked using statistical tests for correlation. The changes in signal regularity are checked by a multifractal spectrum. The probability integral transformation is then applied to cardiovascular time series-systolic blood pressure and pulse interval-acquired from the laboratory animals and represented the results of entropy estimations. We derived an expression for the reference value of entropy in the probability integral transformed signals. We also experimentally evaluated the reliability of entropy estimates concerning the matching probabilities.
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Vasopressin (VP) is a neurohypophyseal peptide best known for its role in maintaining osmotic and cardiovascular homeostasis. The main sources of VP are the supraoptic and paraventricular (PVN) nuclei of the hypothalamus, which coexpress the vasopressin V1a and V1b receptors (V1aR and V1bR). Here, we investigated the level of expression of VP and VP receptors in the PVN of borderline hypertensive rats (BHRs), a key integrative nucleus for neuroendocrine cardiovascular control. Experiments were performed in male BHRs and Wistar rats (WRs) equipped with a radiotelemetry device for continuous hemodynamic recording under baseline conditions and after saline load without or with stress. Autonomic control of the circulation was evaluated by spectral analysis of blood pressure (BP) and heart rate (HR) variability and baroreceptor reflex sensitivity (BRS) using the sequence method. Plasma VP was determined by radioimmunoassay, and VP, V1aR, and V1bR gene expression was determined by RT-qPCR. Under baseline conditions, BHRs had higher BP, lower HR, and stronger BRS than WRs. BP and HR variability was unchanged. In the PVN, overexpression of the VP and V1bR genes was found, and plasma VP was increased. Saline load downregulated V1bR mRNA expression without affecting VP mRNA expression or plasma VP and BP. Adding stress increased BP, HR, and low-frequency sympathetic spectral markers and decreased plasma VP without altering the level of expression of VP and VP receptors in the PVN. It follows that overexpression of VP and V1bR in the PVN is a characteristic trait of BHRs and that sympathetic hyperactivity underlies stress-induced hypertension.
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Hipertensión/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Vasopresinas/metabolismo , Estrés Psicológico/complicaciones , Vasopresinas/sangre , Animales , Barorreflejo , Aglomeración , Femenino , Hipertensión/etiología , Masculino , Distribución Aleatoria , Ratas Endogámicas SHR , Ratas WistarRESUMEN
The chronically increased blood pressure characteristic of essential hypertension represents an insidious and cumulative risk for cardiovascular disease. Essential hypertension is a multifactorial condition, with no known specific aetiology but a strong genetic component. The Spontaneously Hypertensive rat (SHR) shares many characteristics of human essential hypertension, and as such is a commonly used experimental model. The mammalian hypothalamo-neurohypophyseal system (HNS) plays a pivotal role in the regulation of blood pressure, volume and osmolality. In order to better understand the possible role of the HNS in hypertension, we have used microarray analysis to reveal differential regulation of genes in the HNS of the SHR compared to a control normotensive strain, the Wistar Kyoto rat (WKY). These results were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One of the genes identified and validated as being downregulated in SHR compared to WKY was that encoding the neuropeptide urocortin (Ucn). Immunohistochemical analyses revealed Ucn to be highly expressed within magnocellular neurons of the PVN and SON, with pronounced localisation in dendritic projections containing oxytocin and vasopressin. When Ucn was overexpressed in the PVN of the SHR by in vivo lentiviral mediated gene transfer, blood pressure was unaffected but there were significant, transient reductions in the VLF spectra of systolic blood pressure consistent with an action on autonomic balance. We suggest that Ucn may act, possibly via dendritic release, to subtly regulate neurohumoral aspects of arterial pressure control.
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The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg·kg-1·day-1, FA 5 mg·kg-1·day-1; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis.
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Ácido Fólico/administración & dosificación , Ácido Fólico/farmacología , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Vitamina B 6/administración & dosificación , Vitamina B 6/farmacología , Animales , Biomarcadores/metabolismo , Electrocardiografía/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/fisiopatología , Masculino , Monocrotalina/efectos adversos , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Since the discovery of vasopressin (VP) and oxytocin (OT) in 1953, considerable knowledge has been gathered about their roles in cardiovascular homeostasis. Unraveling VP vasoconstrictor properties and V1a receptors in blood vessels generated powerful hemostatic drugs and drugs effective in the treatment of certain forms of circulatory collapse (shock). Recognition of the key role of VP in water balance via renal V2 receptors gave birth to aquaretic drugs found to be useful in advanced stages of congestive heart failure. There are still unexplored actions of VP and OT on the cardiovascular system, both at the periphery and in the brain that may open new venues in treatment of cardiovascular diseases. After a brief overview on VP, OT and their peripheral action on the cardiovascular system, this review focuses on newly discovered hypothalamic mechanisms involved in neurogenic control of the circulation in stress and disease.
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Fenómenos Fisiológicos Cardiovasculares , Hipotálamo/metabolismo , Oxitocina/fisiología , Vasopresinas/fisiología , Animales , HumanosRESUMEN
Using comprehensive analysis of heart rate (HRV) and blood pressure (BPV) short-term variability we estimated the time course of changes of autonomic nervous system remodeling in two stages of doxorubicin-induced cardiomyopathy (DCM). We also investigated the level of gene expression of cardiac ß-1 (ß-1AR) and ß-2 (ß-2AR) adrenoceptors. Experiments were performed in adult male Wistar rats equipped with indwelling catheters for BP recording and blood withdrawal. A 15 mg/kg total cumulative dose of doxorubicin was injected i.p. to rats to induce DCM or saline for control (n=18). Rats were assessed for general toxicity, cardiovascular hemodynamic and echocardiography before treatment (n=6), 35 days (DOX35; n=6) and 70 days (DOX70; n=6) post-treatment. HRV was evaluated by spectral analysis, Poincaré plots, sample and approximate entropy. Expression of ß-1AR and ß-2AR mRNA was evaluated by RT-qPCR. Doxorubicin-treated rats exhibited poor general condition and lower survival than saline-treated rats. In DOX35 rats, there were no echocardiography signs of decompensation, no increase in serum cardiac troponins, but there was an increase of HRV and decrease of HR complexity. In these rats typical microscopic signs of cardiotoxicity were seen along with over-expression of ß-1AR mRNA. 70 days post-treatment echocardiography revealed signs of decompensation and serum cardiac troponin T was increased. At this stage BPV decreased. In conclusion, HRV increase matches transient over-expression of cardiac ß-1AR mRNA in compensate stage of DCM while decompensate stage of DCM is characterized by a decrease of BPV and no changes in ß-1AR and ß-2AR gene expression.
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Antibióticos Antineoplásicos/toxicidad , Cardiomiopatías/inducido químicamente , Doxorrubicina/toxicidad , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Animales , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Ecocardiografía , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratas WistarRESUMEN
We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.
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Indoles/administración & dosificación , Nanoconjugados/química , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/administración & dosificación , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Animales , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/etiología , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Ecocardiografía , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias/patología , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/farmacocinética , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/efectos adversos , Fármacos Fotosensibilizantes/farmacocinética , Ácido Poliglutámico/química , Ratas , Ratas Endogámicas WKY , Distribución TisularRESUMEN
Elderly people exhibit a diminished capacity to cope with osmotic challenges such as dehydration. We have undertaken a detailed molecular analysis of arginine vasopressin (AVP) biosynthetic processes in the supraoptic nucleus (SON) of the hypothalamus and secretory activity in the posterior pituitary of adult (3 months) and aged (18 months) rats, to provide a comprehensive analysis of age-associated changes to the AVP system. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, we identified differences in pituitary peptides, including AVP, in adult and aged rats under both basal and dehydrated states. In the SON, increased Avp gene transcription, coincided with reduced Avp promoter methylation in aged rats. Based on transcriptome data, we have previously characterized a number of novel dehydration-induced regulatory factors involved in the response of the SON to osmotic cues. We found that some of these increase in expression with age, while dehydration-induced expression of these genes in the SON was attenuated in aged rats. In summary, we show that aging alters the rat AVP system at the genome, transcriptome, and peptidome levels. These alterations however did not affect circulating levels of AVP in basal or dehydrated states.
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Envejecimiento/metabolismo , Arginina Vasopresina/biosíntesis , Arginina Vasopresina/genética , Deshidratación/genética , Deshidratación/metabolismo , Sistemas Neurosecretores/metabolismo , Osmorregulación/fisiología , Núcleo Supraóptico/metabolismo , Animales , Arginina Vasopresina/metabolismo , Genoma/genética , Masculino , Espectrometría de Masas/métodos , Metilación , Concentración Osmolar , Neurohipófisis/metabolismo , Regiones Promotoras Genéticas , Ratas Wistar , Transcripción Genética , Transcriptoma/genéticaRESUMEN
PURPOSE OF REVIEW: We present recent advances in understanding of the role of vasopressin as a neurotransmitter in autonomic nervous system control of the circulation, emphasizing hypothalamic mechanisms in the paraventricular nucleus (PVN) involved in controlling sympathetic outflow toward the cardiovascular system. RECENT FINDINGS: Suggest that somato-dendritically released vasopressin modulates the activity of magnocellular neurons in the PVN and SON, their discharge pattern and systemic release. Advances have been made in uncovering autocrine and paracrine mechanisms controlling presympathetic neuron activity, involving intranuclear receptors, co-released neuroactive substances and glia. It is now obvious that intranuclear release of vasopressin and the co-release of neuroactive substances in the PVN, as well as the level of expression of vasopressin receptors, modulate sympathetic outflow to the cardiovascular system and determine vulnerability to stress. Further research involving patho-physiological models is needed to validate these targets and foster the development of more efficient treatment.
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Sistema Nervioso Autónomo/fisiología , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Neurofisinas/fisiología , Precursores de Proteínas/fisiología , Vasopresinas/fisiología , Animales , Sistema Nervioso Autónomo/metabolismo , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Humanos , Hipertensión/metabolismo , Neuronas/metabolismo , Neurofisinas/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Precursores de Proteínas/metabolismo , Receptores de Vasopresinas/metabolismo , Vasopresinas/metabolismoRESUMEN
Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation.