A hipertensão arterial (HA) é um importante problema de saúde pública e representa um dos fatores de risco mais relevantes na etiologia das doenças cardiovasculares. O incremento na resistência vascular periférica (RVP) é a principal característica da HA e está diretamente associado a alterações vasculares estruturais, mecânicas e funcionais. O aumento do estresse oxidativo tem sido considerado um importante fator que contribui para o desenvolvimento e estabelecimento da HA. A prática regular de exercício físico aeróbio, utilizada como medida não farmacológica para o tratamento da HA, tem se mostrado efetiva em reduzir os valores de pressão arterial através da promoção de diversas adaptações cardiovasculares. Este estudo teve como objetivo avaliar os efeitos do treinamento físico (TF) aeróbio sobre as alterações vasculares de artérias coronárias e mesentéricas de resistência induzidas pela HA. Para isso ratos espontaneamente hipertensos (SHR) foram submetidos a um protocolo de TF aeróbio. Este TF promoveu alterações estruturais, avaliadas através de um miógrafo de pressão, como o remodelamento vascular em coronárias e redução de colágeno com aumento na área das fenestras da elastina em mesentéricas, as quais foram associadas com a melhora na rigidez vascular. Além disso, o TF induziu melhora da função endotelial, avaliada através de estudos de reatividade vascular, principalmente mediada por aumento na disponibilidade de óxido nítrico ocasionada por redução do estresse oxidativo. Os resultados sugerem que o TF promoveu alterações vasculares que podem contribuir para diminuir a RVP e reduzir a pressão arterial / Hypertension is a major public health problem and represents one of the most important risk factors in the etiology of cardiovascular diseases. Peripheral vascular resistance increased is the main feature of hypertension and it is directly associated with vascular structural, mechanical and functional alterations. Oxidative stress increased has been considered an important factor that contributes to the development and establishment of hypertension. Regular exercise training, used as a non pharmacological treatment of hypertension, has been effective reducing blood pressure by promoting several cardiovascular adaptations. The aim of the present study was evaluate the effects of treadmill training on the vascular alterations of coronary and mesenteric resistance arteries induced by hypertension. Then, spontaneously hypertensive rats (SHR) were submitted to an aerobic exercise training protocol. The exercise training promoted structural alterations, measured by a pressure myography, as coronary vascular remodeling and collagen reduction and also the area of fenestrae in the elastin of mesenteric arteries were increased, which were associated with vascular stiffness improvement. In addition, the exercise training improved the endothelial function in both arterial beds, as evaluated by vascular reactivity analysis, mediated primarily by increasing nitric oxide availability caused by oxidative stress reduction. The results suggest that exercise training promoted vascular changes that can contribute to reduce peripheral vascular resistance and blood pressure

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-06T14:57:14Z No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-06T20:25:13Z (GMT) No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) / Made available in DSpace on 2017-03-06T20:25:13Z (GMT). No. of bitstreams: 1 gustavomontesnovaes.pdf: 4933394 bytes, checksum: d1148020d41a74584cee8821c8f26603 (MD5) Previous issue date: 2015-07-10 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A hipertensão é uma doença crônica que está relacionada com o aumento da pressão exercida pelo sangue nas paredes dos vasos sanguíneos. Seu surgimento está relacionado a síndromes metabólicas e, frequentemente, á obesidade. Entre o período de 2000 e 2011, esta patologia foi considerada a maior causa de morte no mundo devido à complicações inerentes a sua disfunção, como por exemplo acidente vascular cerebral e o infarto do miocárdio. Diversos estudos vêm sendo realizados com o objetivo de compreender melhor os mecanismos que estão relacionados ao surgimento da hipertensão bem como as disfunções causadas pela doença. Dentre estas disfunções, existem as alterações fisiológicas que ocorrem no coração sendo que as principais alterações ocorrem na atividade elétrica e mecânica do órgão cardíaco. A modelagem computacional se mostra como uma ferramenta muito eficaz no auxílio de tais estudos. A possibilidade de simular as disfunções causadas pela hipertensão no coração permitiria realizar experimentos prévios com baixo custo e em um pequeno intervalo de tempo. Assim este trabalho tem por principal objetivo apresentar modelos computacionais capazes de reproduzir a atividade eletromecânica transmural do miócito de ratos normotensos e hipertensos. Para isto, é proposto um novo modelo matemático/computacional resultado de um acoplamento de outros dois presentes na literatura. O modelo computacional proposto obteve resultados bastante satisfatórios visto que foi capaz de reproduzir as alterações fisiológicas ocorridas em miócitos de ratos, tanto para células de origem do epicárdio quanto para células de origem do endocárdio, nas principais variáveis associadas ao batimento cardíaco: potencial de ação, transiente intracelular de cálcio e o encurtamento do sarcômero. / The hypertension is a chronic disease that is related to an increased in the pressure exerted by the blood on the walls of blood vessels. Its appearance is related to the metabolic syndrome and often with obesity. Between the years 2000 and 2011, this condition was considered the leading cause of death worldwide due to the complications inherent to its dysfunction, such as stroke and myocardial infarction. Several studies have been conducted in order to better understand the mechanisms that are related to the onset of hypertension and the dysfunctions caused by this disease. Among these disorders, there are the physiological changes that occur in the heart with the main changes occuring in electrical and mechanical activity of the heart organ. The Computational modeling can become a very effective tool in aid of such studies. The possibility of simulating the dysfunctions caused by hypertension in the heart would results in a possibility to do previous in silico experiments with low cost and in a short period of time. So this work is primarily engaged to present computational models capable of reproducing the transmural electromechanical activity of myocyte of normotensive and hypertensive rats. For this, a new mathematical / computational model was proposed resulted from a coupling of two others models presented in the literature. The proposed computational model obtained satisfactory results since it was able to reproduce the physiological changes in myocytes of rats, both for epicardial origin of cells and for endocardial cells of origin, the main variables associated with the heartbeat: the action potential, calcium intracellular transient and the shortening of the sarcomere.

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Diplomová práce Abstract - Iveta Brabcová Abstract Ischemia-reperfusion heart injury is one of the most significant diseases affecting mankind and therefore current research pays more attention to its prevention and knowledge of the possible mechanisms which protect the heart. Adaptation to hypoxia has been known for several decades as a cardioprotective intervention but the main issues of protective mechanisms which are induced by the adaptation are still not completely understood. An important role of mitochondria as the main producers of energy and reactive oxygen species which can play a signalizing role in these mechanisms is confirmed in many studies. For this reason a special conplastic strain SHR/OlaIpcv-mtBN/Crl was created. This strain carries the nuclear genome of spontaneously hypertensive rat (SHR) and the mitochondrial genome of normotensive, highly resistant strain Brown Norway (BN). The aim of this study was to compare the expression of selected gene transcripts in the area of energy metabolism, of genes which are related to mitochondrial biogenesis and signaling and antioxidant systems. Comparing the expression was analyzed between strains and after chronic hypoxia adaptation, which cause cardioprotective phenotype in both of these strains. Our results showed a different expression HIF-1α...

The circadian system is an important coordinator of physiological functions of a mammalian organism. It comprises of a central oscillator represented by cells in the suprachiasmatic nuclei of hypothalamus (SCN) and peripheral oscillators in most if not all cells of peripheral tissues. The peripheral oscillators, similarly to the central ones, generate circadian oscillations at the level of so called clock genes and their protein products. In peripheral tissues, oscillations in expression of the individual clock genes are autonomous, however, they need to be synchronized to ensure their robust rhythmic expression. The peripheral clocks are synchronized mainly by rhythmical signals from the SCN, including signals regulating food intake. Disturbances in the clock gene expressions, as well as impaired synchronization signals, can result in various pathophysiological states. Spontaneously hypertensive rat (SHR) strain is a convenient animal model to study potential connection between the disturbed circadian system and progressive development of hypertension and metabolical diseases in mammals. Various studies have shown differences in the rhythmical expression of clock genes between SHR strain and normotensive Wistar/Wistar-Kyoto strain. The aim of this thesis is to provide insight into the early...

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A linhagem de ratos espontaneamente hipertensos (SHR) tem sido utilizada para como modelo animal para hipertensão humana, uma vez que estes animais desenvolvem pressóricos aumentados, hipertrofia ventricular esquerda, aumento de colágeno intersticial e disfunção diastólica. Embora o excesso de colágeno fibrilar tenha sido bem estudado neste modelo e esteja envolvido na insuficiência cardíaca observada, não há estudos quantitativos acurados (baseados na estereologia) para avaliar precisamente o volume tecidual ocupado pelo colágeno fibrilar e o remodelamento das fibrilas de colágeno segundo seu diâmetro uma vez que variações no diâmetro das fibrilas têm grande impacto funcional Mais ainda, nunca foi estudado neste modelo o remodelamento das fibras do sistema elástico (oxitalânicas, elaunínicas e elásticas propriamente ditas), que juntamente com o componente colagênico são responsáveis pelas características biomecânicas do tecido. Assim sendo, os corações de ratos Wistar (WIS), Wistar Kyoto (WKY) e SHR foram submetidos a análise hemodinâmicas e foram processados para microscopia de luz e eletrônica, segundo amostragem estereológica. Cortes corados com HE foram utilizados para avaliação do diâmetro dos cardiomiócitos e do volume absoluto do coração e do ventrículo esquerdo; cortes corados com Picrossirius-hematoxilina foram utilizados para a avaliação da fração de volume ocupada por colágeno no ventrículo esquerdo e volume absoluto de colágeno; cortes ultra-finos foram utilizados para avaliação do diâmetro das fibrilas de colágeno cortadas transversalmente e para avaliação da distribuição das fibras oxitalânicas, elaunínicas e elásticas. Os resultados mostram que a hipertrofia ventricular dos animais SHR deveu-se à hipertrofia dos cardiomiócitos associada à maior quantidade de colágeno fibrilar (3,8 x maior no SHR que no WIS). A análise ultraestrutural mostrou que as fibrilas de colágeno no endomísio variam, em nanômetros, de 31 a 53 nos animais WIS, de 36 a 67 nos WKY e de 31 a 85 nos SHR, com medianas respectivamente de 39,58, 48,38 e 54,39, sendo que do ponto de vista estatístico a distribuição dos diâmetros das fibrilas colágenas dos animais SRH é diferente das outras duas linhagens.A análise uttra-estrutural das fibras do sistema elástico mostrou que as fibras oxitalânicas, elaunínicas e elásticas apresentam uma distribuição diferencial nos diversos compartimentos da parede cardíaca dos animais, sendo que nas três linhagens há fibras elásticas propriamente ditas no endocárdio e epicárdio; no entanto, no perimísio as fibras elásticas e elaunínicas aparecem raramente nos ratos SRH e com maior freqüência nos WIS e WKY; no endomísio dos ratos SRH não foi possível observar a mesma riqueza de fibras elásticas e elaunínicas presentes nas outras linhagens, havendo assim um predomínio de fibras oxitalânicas no vi endomísio dos animais SHR. Os resultados mostram que, além das modificações quantitativas no conteúdo de colágeno no miocárdio do ventrículo esquerdo dos animais SHR, há também uma alteração qualitativa na população de fibrilas colagênicas que passa a ser constituída por fibrilas mais grossas. Mais ainda, os resultados mostram que, em relação às fibras do sistema elástico, a predominância de fibras oxitalânicas no endomísio dos animais SHR sugere que as forças de tensão maiores no coração destes animais modulem não somente o sistema colagênico mas também o sistema elástico no sentido de acumular fibras que suportam melhor as cargas, contribuindo para a perda da complacência da parede ventricular / The strain of spontaneously hypertensive rats (SHR) has been used as an animal model for human hypertension, since these animals develop increased blood pressure, left ventricular hypertrophy, increased interstitial collagen and diastolic dysfunction. Although excess fibrillar collagen has been well studied in this model and is involved in observed heart failure, there are no accurate quantitative studies (i.e., based on stereology) to precisely assess the volume of tissue occupied by fibrillar collagen neither the remodeling of collagen fibrils with respect to their diameters, and such studies are very important because variations in the diameter of the fibrils have a major functional impact. Moreover, the remodeling of elastic system fibers (oxytalan, elauninic and elastic proper), which together with the collagenous component are responsible for biomechanical features of the tissue, has never been studied in this model. Thus, the hearts of Wistar (WIS), Wistar Kyoto (WKY) and SHR rats went through hemodynamic analysis and were processed for light and electron microscopy, according to stereological sampling criteria. HE-stained sections were used to evaluate the diameter of the cardiomyocytes and the absolute volume of the heart while left ventricular sections stained by Picrosirius-hematoxylin were used to evaluate the volume fraction occupied by collagen in the left ventricle as well as its absolute volume of collagen; ultra-thin sections were used for evaluation of the diameter of transversally sectioned collagen fibrils and for evaluation of the distribution of oxytalan, elauninic and elastic proper fibers. The results show that the ventricular hypertrophy of SHR rats was due to cardiomyocyte hypertrophy associated with a higher amount of fibrillar collagen (3.8 times as high as in the WIS rats). The ultrastructural analysis showed that the collagen fibrils in the endomysium range in nanometers, from 31 to 53 in WIS animals, 36 to 67 in the WKY and 31 to 85 in SHR, with medians 39.58, 48.38 and 54.39, respectively. The distribution of diameters of collagen fibrils is statistically different in SRH animals when compared to the other two strains. The ultrastructural analysis of the fibers of the elastic system showed that oxytalan, elauninic and elastic fibers present a differential distribution across the various compartments of the heart wall of the animals. In the three strains there are elastic fibers proper in the endocardium and epicardium, while in the perimysium, the elastic fibers proper and the elauninic fibers rarely appear in SRH rats, being more frequent in WIS and WKY rats; the endomysium of SRH rats did not exhibit the same richness of elastic fibers proper and elauninic fibers present in other strains, occurring thus a predominance of oxytalan fibers in the endomysium of SHR rats. viii The results also show that, in addition to the quantitative changes in collagen content of left ventricular myocardium of SHR rats, there is a qualitative alteration in the population of collagen fibrils that is richer in thicker fibrils. Moreover, the results show that, with respect to the fibers of the elastic system, the predominance of the oxytalan fibers in the endomysium of SHR rats suggests that the higher tensile forces in the hearts of these animals modulate not only the collagenous system but also the elastic system, entailing accumulation of fibers suited to better support the loads, contributing to the loss of ventricular wall compliance

O aumento da osmolaridade plasmática é conhecido como hiperosmolaridade e é resultado do aumento do aporte de sódio ou, da diminuição do volume plasmático de água. Trata-se de um desafio orgânico capaz de iniciar uma série de respostas neuro-hormonais que incluem a liberação de vasopressina e aumento da atividade simpática, com consequente elevação da pressão arterial. Descrever o papel do sistema nervoso autonômico no desenvolvimento da hipertensão arterial secundária a ingestão de sódio é essencial para elucidar os mecanismos envolvidos na gênese desta patologia. Neste sentido, o RVLM é um importante alvo de estudos, dado seu envolvidos na regulação da atividade simpática, via projeções para a CIML. O RVLM possui um grupo neuronal denominado C1 caracterizado pela presença da enzima PNMT; a ativação destes neurônios já foi descrita em resposta a diversos desafios orgânicos tais como hipóxia, dor, hemorragia, inflamação, hipotensão e hipoglicemia. Sendo a hiperosmolaridade um desequilíbrio da homeostase propusemos investigar a possível participação dos neurônios adrenérgicos do grupamento C1 sobre a hipertensão secundária ao desafio hiperosmótico desencadeado pela ingestão crônica de solução de 2% cloreto de sódio (salina hipertônica de NaCl 2%) por 7 dias. Nossos resultados nos permitem concluir que: 1) a injeção de anti-D&betaH-saporina na região do RVLM causou a depleção de neurônios TH+ nas regiões C1 e A5; 2) A depleção dos neurônios TH+ não alterou o comportamento de ingestão de sódio e, tampouco os valores de hematócrito e osmolaridade plasmática resultados da exposição ao hiperosmótico durante 7 dias, comparado aos animais controle; 3) A lesão prévia dos neurônios do C1 e A5 inibe o desenvolvimento da hipertensão secundária ao estímulo hiperosmótico por ingestão de NaCl 2%. Além disso, propusemos também estudar como estariam as respostas cardiovasculares e de controle hidroeletrolítico em indivíduos normotensos e previamente hipertensos frente a diferentes intensidades de estímulo hiperosmótico desencadeado pela ingesta de salina hipertônica de NaCl 2%. Os resultados demonstraram que 1) a ingestão de sódio desencadeia uma elevação da pressão arterial de maior magnitude nos SHR, quando comparado aos animais Wistar; 2) que não parece estar envolvida com diferenças no balanço hidroeletrolítico, uma vez que observou-se repostas similares entre as duas linhagens; 3) houve ainda, um aumento da expressão do RNAm para neuropeptídeo vasopressina (VP) no núcleo paraventricular do hipotálamo (PVN) tanto em Wistar quanto em SHR decorrente da ingestão de NaCl 2% durante 7 dias. Até o presente momento nossos resultados permitem duas considerações acerca dos mecanismos envolvidos nas repostas geradas frente desafios da osmolaridade: 1) os neurônios TH+ e, potencialmente do grupamento C1, estão envolvidos no desenvolvimento da hipertensão arterial em situações de desafio crônico da osmolaridade; 2) em animais hipertensos (SHR) o estímulo hiperosmótico gera uma elevação da pressão arterial de maior magnitude em comparação aos animais normotensos, fato que sugerimos envolver mecanismos de controle neural da pressão arterial, uma vez que não se observou alterações significativas nos parâmetros hidroeletrolítico e função renal entre as duas linhagens. / Plasma osmolarity increases is known as hyperosmolarity and it is a consequence of high sodium intake or decrease of water plasma content. It is an organic imbalance that elicits neurohormonal responses including release of vasopressin and increased in sympathetic activity, with consequent elevation of blood pressure. To describe the role of the autonomic nervous system in the development of sodium induced hypertension is critical to elucidate the mechanisms involved in the genesis of this pathology. In this sense, the RVLM is an important target, given its involved in the regulation of sympathetic activity, via CIML projections. The RVLM has a neuronal group known as C1 that present the PNMT enzyme; the activation of these neurons has already been described in response to several organic challenges such as hypoxia, pain, hemorrhage, inflammation, hypotension and hypoglycemia. Since hyperosmolarity is an homeostasis imbalance, we propose to investigate the role of adrenergic C1 neurons on sodium induced hypertension, triggered by the chronic ingestion of NaCl2% solution during 7 days. Our results allow us to conclude that: 1) the anti-D&betaH-saporin injection in the RVLM led to a depletion of TH+ neurons in the C1 and A5 regions; 2) Depletion of TH + neurons did not alter the sodium intake behavior, hematocrit and plasma osmolality values result from 7 days NaCl 2% exposure, compared to control animals; 3) Depletion of TH+ in C1 and A5 regions inhibits the development of sodium induced hypertension . In addition, we also proposed to investigate the cardiovascular and hydroelectrolytic responses elicits in normotensive and hypertensive rats, in response to different intensities of hyperosmotic stimulation triggered by the ingestion of hypertonic saline of NaCl 2%. The results demonstrated that: 1) the increase in blood pressure triggers by NaCl 2% intake is higher in SHR when compared to Wistar animals; 2) that does not appear to be involved with differences in hydroelectrolyte balance, since similar responses were observed between the two strains; 3) there was also an increase in mRNA expression for neuropeptide vasopressin (VP) in the paraventricular nucleus of the hypothalamus (PVN) in both strains, Wistar and SHR, in consequence of 7 days NaCl 2% intake. Our results allow two considerations about the mechanisms involved in the responses elicits by osmolarity challenges: 1) TH+ neurons and, potentially C1 neurons, are involved in the development sodium induced hypertension and; 2) in SHRs the hyperosmotic stimulus generates a higher blood pressure increase in comparison to normotensive animals, which seems to be associated with sympathoexcitatory components, since no significant alterations were observed in the hydroelectrolytic parameters and renal function between the two strains.

<p>This thesis investigates aspects of field theories and soliton solutions with nontrivial topology. In particular we explore the following effective models: a limited sector of the scalar Electroweak theory called extended Abelian Higgs model, and a classical mechanics model derived from the low energy SU(2) Yang-Mills theory.</p><p>The extended Abelian Higgs model applied on two-component plasma of charged particles is studied numerically. We find evidence that the model admits straight twisted line vortices. The result is described by an energy function that acquires a minimum value for a non-trivial twist. In addition to the twisted line vortices the result also suggests that stable torus shaped solitons are solutions of the theory. </p><p>Furthermore we construct a classical mechanics model exhibiting some of the key properties of the low-energy Yang-Mills theory. The dynamics of the model is studied numerically. We find that its classical equations of motion support stable periodic orbits. In a three dimensional projection these trajectories are self-linked in a topologically non-trivial manner suggesting the existence of knotted configurations in low energy SU(2) Yang-Mills theory. </p><p>We calculate the one-loop effective action for the Abelian Higgs model with extended Higgs sector. The resulting first order quantum corrected model shows close resemblance to a modified model where texture stabilizing term has been added to the system. In the limit where the gauge field can be entirely expressed by the scalar fields, the both models become identical suggesting that the theories are closely connected. This implies that quantum corrections have stabilising effect on the soliton solutions. </p><p>These studies have contributed to a better understanding of the dynamics of non-linear low energy systems, and brought us a step closer to exploring full scale physically realistic models.</p>

This thesis investigates aspects of field theories and soliton solutions with nontrivial topology. In particular we explore the following effective models: a limited sector of the scalar Electroweak theory called extended Abelian Higgs model, and a classical mechanics model derived from the low energy SU(2) Yang-Mills theory. The extended Abelian Higgs model applied on two-component plasma of charged particles is studied numerically. We find evidence that the model admits straight twisted line vortices. The result is described by an energy function that acquires a minimum value for a non-trivial twist. In addition to the twisted line vortices the result also suggests that stable torus shaped solitons are solutions of the theory. Furthermore we construct a classical mechanics model exhibiting some of the key properties of the low-energy Yang-Mills theory. The dynamics of the model is studied numerically. We find that its classical equations of motion support stable periodic orbits. In a three dimensional projection these trajectories are self-linked in a topologically non-trivial manner suggesting the existence of knotted configurations in low energy SU(2) Yang-Mills theory. We calculate the one-loop effective action for the Abelian Higgs model with extended Higgs sector. The resulting first order quantum corrected model shows close resemblance to a modified model where texture stabilizing term has been added to the system. In the limit where the gauge field can be entirely expressed by the scalar fields, the both models become identical suggesting that the theories are closely connected. This implies that quantum corrections have stabilising effect on the soliton solutions. These studies have contributed to a better understanding of the dynamics of non-linear low energy systems, and brought us a step closer to exploring full scale physically realistic models.