DSpace Collection:http://hdl.handle.net/1843/2142024-03-28T17:26:35Z2024-03-28T17:26:35ZEfeitos do estradiol na memória e comportamentos afetivos causados pela privação de hormônios ovarianoshttp://hdl.handle.net/1843/658832024-03-14T17:03:30Z2015-05-20T00:00:00ZTitle: Efeitos do estradiol na memória e comportamentos afetivos causados pela privação de hormônios ovarianos
Abstract: Cognitive and affective disorders occurred during the menopause impact woman’s quality of life and reflect impairments in brain function caused by the estrogens decline. The aim of the present study was to investigate the molecular and functional alterations in the brain of female mice that underwent to hormone deprivation. We also investigated the acute affect of estradiol (E2) in these alterations. Ovariectomy (OVX) surgery was used as a model to induce hormonal depletion in mice. Behavioral analyses demonstrated that 12 weeks of OVX is a critical time-point to observe cognitive and affective impairments. OVX changed the expression of estrogen receptors (ERs) in the hippocampus (HIP) and also modified the c-Fos expression in the amygdala (AMY) after cued fear conditioning. Furthermore, in a genetic mice model for obsessive-compulsive disorder (OCD), the OVX worsened the compulsive- and anxiety-like behaviors, although did not change the memory deficit already founded. On the other hand, the estradiol (E2) administration recovered the impairments observed in OCD female mice model. After 12 weeks of OVX, the administration of E2 and agonists of ERs were effective in decreasing the depressive-like behavior, the HIP-dependent memory deficit. However, E2 was ineffective to rescue the anxiety-like behavior and cued fear memory impairment caused by OVX. Together, our results support the hypothesis that long-term ovarian hormones deprivation is able to promote molecular and functional changes in the brain of female mice, as well as worsen the behavioral alterations observed in the OCD mice model. In addition, we demonstrated that acute E2 administration was able to minimize most of the cognitive and affective impairments evaluated, although its effect was more expressive in HIP-dependent functions. Finally, an important finding of the present study was the suggestion that long-term OVX modify the amygdaloid complex excitability, which may compromise the AMY-dependent memory.
Type: Tese2015-05-20T00:00:00ZParticipação do óxido nítrico central nos ajustes termorregulatórios durante o exercício físico em ratos espontaneamente hipertensos: efeitos do treinamento físicohttp://hdl.handle.net/1843/657752024-03-13T18:50:52Z2018-04-26T00:00:00ZTitle: Participação do óxido nítrico central nos ajustes termorregulatórios durante o exercício físico em ratos espontaneamente hipertensos: efeitos do treinamento físico
Abstract: Thermoregulation occurs by a balance between the mechanisms of heat production and dissipation of the body. The increased availability of nitric oxide (NO) appears to increase heat dissipation and decrease heat storage during exercise. Spontaneously hypertensive rats (SHR) present an imbalance in the regulation of body temperature during physical exercise that may be related to the level of activation of NO-modulated neural pathways. Since physical training could correct thermoregulatory imbalance in SHRs via modulation of central oxynitrogenic pathways, this study aimed to verify if the thermoregulatory deficit presented by hypertensive animals during exercise involves the activation of neural pathways modulated by nitric oxide and which would be the possible effects of physical training on this thermoregulatory control. We used 38 normotensive Wistar rats (NWRs) and 30 SHRs divided into 4 experimental protocols. In the first experimental protocol, the objective was to verify if thermoregulatory deficit presented by hypertensive animals during the exercise would involve changes in the central nervous system. In the second experimental protocol, the objective was to determine the central injection dose of sodium nitroprusside (NPS, a nitric oxide donor) more suitable for the experiments involving thermoregulation during exercise. In the third experimental protocol, the objective was to study the effects of increased NO availability in the central nervous system on the thermal balance during exercise and on physical performance in normotensive and hypertensive rats. In the fourth experimental protocol, the objective was to evaluate the effects of physical training in hypertensive and normotensive rats on the thermal balance during exercise, on the protein expression of neuronal nitric oxide synthase in central nervous system areas involved in thermoregulation during exercise. The results of the study indicate that hypertensive animals present a lower heat dissipation during exercise, which generates greater increases in internal temperature. The difficulty of hypertensive animals in dissipating heat during exercise is, at least in part, related to central mechanisms. Reduced activations of brain nuclei involved in thermoregulation are related to a high threshold for heat dissipation found in hypertensive animals. The dose of 8.4 mmol showed the most adequate dose among those tested to evaluate the effects of NPS on thermoregulation during exercise. Increased central NO availability increases heat dissipation and decreases hyperthermia during exercise in normotensive and hypertensive rats. In addition, physical training increases the efficiency ofthermoregulatory control during exercise in normotensive and hypertensive animals and the increase in this efficiency can be explained by an increase in the activity of neuronal nitric oxide synthase in trained animals. The results of present study allow us to conclude that the thermoregulatory changes found between hypertensive and normotensive animals during exercise originated in the central nervous system. In addition, physical training increases the efficiency of thermoregulatory control during exercise in normotensive and hypertensive animals by increasing the availability of NO in the central nervous system.
Type: Tese2018-04-26T00:00:00ZEfeitos cardiovasculares e renais induzidos pela infusão central de alamandina em animais hipertensoshttp://hdl.handle.net/1843/657712024-03-13T17:46:12Z2018-05-23T00:00:00ZTitle: Efeitos cardiovasculares e renais induzidos pela infusão central de alamandina em animais hipertensos
Abstract: Background and aim. The treatment of hypertension advanced a lot in the last decades, nevertheless around 20% of the subjects with hypertension have a condition named resistant hypertension and do not respond well to the currently available therapy. Among the mechanisms involved in the genesis and maintenance of hypertension we highlight the overactivity of angiotensin (Ang) II-AT1 receptor axis of the circulating and tissue reninangiotensin system (RAS), including the brain RAS, which is associated to an imbalance of the autonomic nervous system activity. Recently, a new axis of the RAS composed by alamandine and MrgD receptor was described. The studies done heretofore show that alamandine has similar biological effects to those demonstrated to Ang-(1-7), suggesting that this axis could be an additional contraregulatory mechanism of the RAS. The aim of this study was to investigate the effects of the increased levels of alamandine in the central nervous system on cardiovascular parameters, the heart, the kidney, and the brain of hypertensive animals. Methods. To perform this study, Sprague-Dawley (SD) rats and two experimental models of hypertension were used: transgenic hypertensive rats, TGR(mREN2)27 (TG), and DOCA-Salt hypertensive rats (DOCA). Part of the animals received treatment with short-term intracerebroventricular (ICV) infusion of alamandine (90 minutes), and another part of the animals received treatment with long-term ICV infusion of alamandine (14 or 28 days, with osmotic minipumps). The assessment of cardiovascular parameters (arterial pressure, heart rate, and baroreflex sensitivity) was carried out through one of the following methods: arterial pressure acquisition system (AP, BIOPAC), telemetry, or by tail-cuff pletismography. Damage in the heart and kidney was evaluated by the following parameters: 1) cardiac hypertrophy by the heart weight and cardiomyocytes diameter by histology and gene expression (mRNA) of two hypertrophy markers: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); 2) assessment of extracellular matrix deposition by histology and gene expression (mRNA) of extracellular matrix proteins in the left ventricle of the heart (LV) and in the kidney; 3) cardiac function by echocardiogram; 4) measurement of inflammatory mediators in the LV and kidney (ELISA); 5) evaluation of inflammatory infiltrate and tubulointerstitial injury in the kidney by histology; 6) renal function assessment. The possible brain mediators involved on alamandine effects were evaluated by: 1) RNASeq; 2) gene expression of components of the nitrergic (nNOS), glutamatergic (glutaminase, excitatory aminoacid transporter, and NR1 subunit of the NMDA receptor) systems, and of the RAS [angiotensinogen, angiotensin converting enzyme (ACE), ACE2, MrgD and Mas receptors]; and 3) measurement of inflammatory mediators (ELISA). Results. The short-term (hours) increased levels of alamandine in the CNS decreased the APof hypertensive animals and improved the baroreflex sensitivity in both normotensive and hypertensive rats. The long-term (4 weeks) ICV infusion of alamandine decreased the arterial pressure (SAP, DAP, and MAP) and heart rate of 12 weeks old TG rats. The ICV infusion of alamandine (2 weeks) improved the baroreflex sensitivity of DOCA rats, without changing the AP of these rats. The long-term ICV infusion of alamandine did not change cardiac hypertrophy in both experimental models of hypertension but attenuated the increased extracellular matrix deposition observed in the LV of TG hypertensive rats. The cardiac function and levels of inflammatory cytokines were not changed. Regarding the kidney, the treatment with alamandine decreased the inflammatory infiltrate, the tubulointerstitial injury, the levels of TNF-α, IL-6, and IL-1β, and reverted collagen deposition in TG rats. Concerning central mechanisms of alamandine, TG rats presented increased levels of proinflammatory cytokines in hypothalamus and medulla oblongata. The treatment with alamandine attenuated these changes. There was no change between groups regarding the expression of the RAS components, with exception of the MrgD receptor, which expression is increased in hypertensive rats and is not influenced by the increased levels of alamandine. About the expression of the glutamatergic and nitrergic systems components, we did not find important differences between groups. The expression of a great number of genes is changed in the brain of hypertensive animals and hypertensive animals treated with alamandine. Some of these genes are common to these two groups, nonetheless the changes observed in the expression of these genes is not uniform. Thus, the expression of some genes is increased or decreased in the two groups while other genes present opposite changes in hypertensive animals in comparison to the treated hypertensive animals. Conclusion. Together, the results of this study support the importance of the brain RAS in the pathophysiology of hypertension and indicate alamandine as an alternative and contraregulatory pathway of the RAS.
Type: Tese2018-05-23T00:00:00ZEstudo do papel do Sry no sistema cardiovascular e sua interação com o sistema renina angiotensinahttp://hdl.handle.net/1843/657692024-03-13T17:21:47Z2014-12-18T00:00:00ZTitle: Estudo do papel do Sry no sistema cardiovascular e sua interação com o sistema renina angiotensina
Abstract: The systemic arterial hypertension (SAH) is a multifactorial, polygenetic and sexlinked medical condition characterized by high and sustained levels of blood pressure (BP). One of the components of the complex network that regulates PA is the renin angiotensin system (RAS), which influences the homeostasis of salt and water and vascular tone, has been extensively studied in correlation with hypertension and cardiovascular disease. The SRA can be basically divided into a vasoconstrictor axis (ACE/ANG II/AT1) and a vasodilator axis (ACE2/ANG 17/MAS/AT2) directly correlated to regulation via the MAP kinases: ERK 1/2, JNK and p38. Many studies show that there is a higher incidence of hypertension and CVD in men compared to women. Recently, studies have demonstrated the involvement of the Sry locus on the Y chromosome in the interaction with the SRA of rats. The aim of this study was to analyze the role of human Sry gene in the regulation of blood pressure and renin angiotensin system of mice strains Sprangue Dawley (SD); and evaluate in primary culture of neonatal rat cardiomyocytes SD and Wistar its interaction with the renin angiotensin system. Sprangue Dawley rats were subjected to the techniques of electroporation and transfection by renal carbon nanotubes multi-walled (NTCPM) for delivery of clones containing Sryh (P Sryh ) and Sry3 (P Sry3 )
via carotid and were monitored by telemetry for blood pressure. The viability was checked by transfection of light and transmission electron microscopy. From the transfection of Sryh , Sry3, siSry and siMas, functionalized with NTCPM, there was a relationship of Sry to the following: regulation of blood pressure, heart rate, gene expression of RAS, expression of t y r o sin e h y d r o x yla s e and ERK1 / 2, JNK and p38. The results obtained by microscopy confirmed the transfection and telemetry showed a significant increase in blood pressure and heart rate of the animals transfected with Sry3 and Sryh when compared to controls, similar to the data obtained by the technique of kidney electroporation. After transfection into cardiomyocytes of SD and Wistar rats with Sryh , there was a significant increase in the expression of the of renin , ACE , AT2 , TH , JNK and ERK 1/2 but decrease in the expression of p38; without significant changes to AT1,
ACE2 and
MAS . We also observed by flow cytometry, an increase in the size and granularity of cardiomyocytes after treatment, which were confirmed by HE and immunofluorescence techniques. These data suggest the involvement of Sry in hypertrophy mechanism. By inhibiting the expression of the genes Sry and MAs by siRNA technique, there is a regulatory effect on Sry receptor but probably via the inhibition of MAP kinases, JNK and ERK 1/2. However, Sry3 produced a significant increase in blood pressure of SD rats in the same way reported in the literature for Wistar Kyoto, showing that Sry has physiological actions conserved in the studied strains of R a tt u s n o r v e gic u s . The Sryh regulates blood pressure, interferes with gene expression of the vasoconstrictor via the SRA, and the precursor pathway of catecholamines from the increased expression of tyrosine hydroxylase. The latter probably due to increased expression of AT2 receptor.
Type: Tese2014-12-18T00:00:00Z