Le système endothéline (ET) est activé en condition d’hypertension pulmonaire (HTP). L’efficacité des antagonistes des récepteurs à l’ET a clairement été démontrée et a menée à l’approbation clinique de tels antagonistes dans le traitement de l’hypertension artérielle pulmonaire (HTAP). Toutefois, il existe présentement un important débat opposant l’utilisation d’un antagoniste sélectif des récepteur ETA à l’utilisation d’un antagoniste double ETA/ETB dans le traitement de cette pathologie. Bien que nous sachions que le système ET est activé et contribue à l’HTAP, les modifications locales de ce système induites par la pathologie, particulièrement au niveau des artères de résistance pulmonaires, demeurent inconnues. De plus, l’impact de ces modifications sur la réponse pharmacologique aux divers antagonistes des récepteurs à l’ET (sélectifs versus double) est d’une importance capitale. Ainsi, le but de la première étude de cette thèse était d’évaluer les modifications potentielles de la pharmacologie du système ET au niveau des artères de résistance pulmonaires induites par l’HTAP. Dans cette étude, nous avons démontré qu’en condition contrôle l’antagoniste sélectif ETA et l’antagoniste double n’ont eu aucun effet sur la réponse vasoconstrictrice à l’ET-1. Toutefois, en condition d’HTAP, les antagonistes sélectif et double ont tous deux été en mesure de réduire la vasoconstriction pulmonaire induite par l’ET-1. Une diminution importante de l’expression génique du récepteur ETB pourrait être à l’origine de cette modification du profil pharmacologique des antagonistes. Une meilleure compréhension des rôles joués par les récepteurs ETA et ETB au niveau des artères de résistance pulmonaires pourrait permettre l’optimisation des traitements de l’HTAP. Ainsi, le but de la deuxième étude était d’évaluer les effets d’un traitement antisens ex vivo dirigé contre l’ARNm des récepteurs ETA et ETB dans la vasoconstriction des artères de résistance pulmonaires induite par l’ET-1. Dans cette étude, nous avons démontré dans un premier temps que les récepteurs ETA et ETB pouvaient former des dimères au niveau des artères de résistance pulmonaires. De plus, nous avons observé qu’une réduction de l’expression protéique du R-ETA entraînait une potentialisation de la vasoconstriction ETB dépendante suggérant ainsi qu’en condition contrôle, le récepteur ETA aurait un effet inhibiteur sur la vasoconstriction pulmonaire induite par la stimulation du récepteur ETB. Les effets délétères de l’ET-1 sur la circulation pulmonaire sont bien connus, toutefois seules quelques études ont porté leur attention sur l’implication de l’ET-3 dans l’HTAP. Ainsi, le but de la troisième étude était d’évaluer l’implication potentielle de l’ET-3 dans l’HTAP. Dans cette étude, nous avons démontré qu’il était nécessaire en condition contrôle de bloquer simultanément les récepteurs ETA et ETB afin de réduire la réponse vasoconstrictrice pulmonaire à l’ET-3. En condition d’HTAP, nous avons observé une augmentation non-significative des concentrations plasmatiques d’ET-3 ainsi qu’une modification du profil pharmacologique des antagonistes des récepteurs à l’ET. En effet, l’utilisation de l’antagoniste sélectif ETA ou de l’antagoniste double était dans les deux cas en mesure de réduire la vasoconstriction pulmonaire à l’ET-3. Les résultats de ces trois études suggèrent qu’il est préférable d’utiliser un antagoniste double dans le traitement de l’HTAP. En effet, (1) en condition d’HTAP, l’utilisation d’un antagoniste double est aussi efficace que l’utilisation d’un antagoniste sélectif ETA; (2) les récepteurs ETA et ETB peuvent former des dimères au niveau des artères de résistance pulmonaires et (3) le récepteur ETB joue un rôle prédominant dans la vasoconstriction pulmonaire, il semble donc essentiel de bloquer simultanément les récepteurs ETA et ETB afin d’inhiber la réponse vasoconstrictrice induite par l’ET. Mots-clés: endothéline-1, endothéline-3, artère de résistance pulmonaire, récepteur vasculaire, antagoniste des récepteurs à l’ET, dimérisation, phosphorothioate, hypertension artérielle pulmonaire / The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH); indeed, increased plasma levels of ET-1 were detected in patients with various forms of PAH and in various experimental models. The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. Whether the net effect of either selective ETA receptor blockade or combined ETA/ETB receptor blockade provides greater therapeutic benefit remains a subject of debate. Although the ET system contributes to PAH, we currently incompletely comprehend which local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists. The purpose of the first study was therefore to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline-induced PAH. Our results reveal striking changes in pulmonary vasculature sensitivity to ET receptor antagonism in PAH that may be related to a reduction in ETB receptor expression. A better understanding of the exact role played by both ETA and ETB receptors on pulmonary resistance arteries might contribute to optimization of PAH treatments. Therefore the aim of the second study was to clarify the role played by both ETA and ETB receptors in ET-1 induced pulmonary vasoconstriction using an antisense (AS) oligonucleotide ex vivo treatment. In this study we have demonstrated that ETA and ETB receptors can form heterodimers in pulmonary resistance arteries. Furthermore, suppression of ETA receptors potentiated the response to ET-1 suggesting that in control condition the ETA receptor has an inhibitory action on the ET-1 induced pulmonary vasoconstriction induced by the stimulation of the ETB receptor. Although the deleterious effects of ET-1 on the pulmonary circulation are well established, only a few studies have focused on ET-3 in PAH. Therefore, the purpose of the last study was to evaluate the potential implication of ET-3 in MCT-induced PAH and evaluate the roles of ETA and ETB receptors on ET-3-induced pulmonary vascular reactivity. In control condition, the use of a combination of both ETA and ETB receptor antagonists is necessary to reduce the ET-3 induced pulmonary vasoconstriction. In PAH, we found an increased ET-3 plasma levels and a modification of the pharmacological profile of ET receptor antagonists. Indeed, the use of either the ETA receptor antagonist or the dual antagonist was able to reduce the ET-3 response. The results from these three studies suggest that it is preferable to use a dual antagonist in the treatment of PAH. Indeed, (1) in PAH the use of a dual antagonist is as effective as the use of a selective ETA receptor antagonist (2) ETA and ETB receptors can form heterodimers in pulmonary resistance arteries and (3) ETB receptor plays an important role in the ET-1 induced pulmonary vasoconstriction, suggesting that it is necessary to block both receptors to reduce the ET-1 induced pulmonary vasoconstriction. Keywords: endothelin-1, endothelin-3, pulmonary resistance artery, receptor, endothelin receptor antagonist, dimerisation, phosphorothioate pulmonary arterial hypertension

La sténose de l’artère rénale (SAR) est à l’origine d’une néphropathie dite « ischémique », dont les mécanismes conduisant au développement d’une insuffisance rénale sont mal connus. Il est utile de savoir à partir de quel degré de SAR surviennent des modifications hémodynamiques significatives dans le rein d’aval, et si une SAR chronique et hémodynamiquement significative peut entraîner une hypoxie rénale. Nous avons donc entrepris 2 études afin de préciser le lien entre degré de SAR et baisse du débit sanguin rénal (DSR), et de rechercher l’apparition d’une hypoxie dans le rein situé en aval d’une SAR chronique. Les résultats de la première étude montrent que la baisse du DSR reste modeste tant que le degré de SAR n’a pas dépassé 70%. Ces résultats nous permettent de conclure qu’une SAR de degré inférieur à 70% n’est probablement associée qu’à des modifications hémodynamiques mineures dans le rein d’aval. Dans la deuxième étude, nous avons décrit l’évolution du contenu rénal en oxygène (CRO) sur une période de 4 semaines après induction d’une SAR chez des rats. La méthode utilisée était l’IRM BOLD, qui permet d’étudier le CRO de manière non-invasive en mesurant le paramètre R2* dont la valeur est inversement proportionnelle au CRO. La mesure hebdomadaire de R2* dans le cortex, la médullaire externe et la partie externe de la médullaire externe des reins sténosés et des reins controlatéraux ne variaient pas au cours de l’étude, malgré l’apparition progressive d’une atrophie des reins en aval de la SAR. Ces données tendent à montrer qu’il n’y a pas d’hypoxie rénale dans notre modèle, et que l’atrophie rénale observée n’est donc pas secondaire à l’hypoxie / Renal artery stenosis (RAS) can lead to a so-called “ischemic” nephropathy but the mechanisms responsible for the development of chronic kidney disease in kidney downstream the RAS are largely unknown. There is an interest to know the degree of RAS that involves significant hémodynamic changes in the downstream kidney and if hypoxia occurs in this case. Therefore, we have undertaken two studies in order to describe the link between RAS degree and renal blood flow (RBF) and to search for the development of renal hypoxia in kidney downstream the RAS. Findings of the first study were that only a minor decrease of RBF occurs until the RAS degree reach 70%. We can thus conclude from these results that RAS degree must be at least of 70% to have hemodynamical repercussions in downstream kidney. In the second study, we describe the evolution of renal oxygen content (ROC) before and during 4 weeks after the constitution of RAS. ROC was measured weekly by the MRI BOLD technique, who allows to study ROC non-invasively by measuring the parameter called R2* that is inversely proportional to ROC. The value of R2* in the cortex, the outer medulla and the outer stripe of outer medulla in stenotic kidneys and controlateral kidneys was unchanged instead the development of atrophy of the kidney downstream the RAS. These results suggest that no renal hypoxia occur in this model and that renal atrophy is not caused by hypoxia

Introdução: A hipertensão arterial é de causa multifatorial, envolvendo hábitos de vida e estilos de vida inadequados como o consumo excessivo de bebida alcoólica que propiciam a elevação dos níveis pressóricos. Além disso, os sintomas relacionados ao transtorno mental comum também podem se associar ao estado de saúde, provocando mais danos ao sujeito com hipertensão arterial. Diante disso, o presente estudo teve como objetivo principal identificar associação entre a ocorrência de hipertensão arterial com o consumo de bebidas alcoólicas e a presença de transtorno mental comum em indígenas das aldeias Muras, residentes em região rural e urbana. Casuística e Métodos: Estudo transversal, de base populacional, com 455 indígenas Mura residentes no município de Autazes, Amazonas, Brasil. Foi aplicada a entrevista semi-estruturada com questões referentes aos dados socioeconômicos e educacionais, hábitos de vida, história clínica, histórico familiar, além dos questionários Alcohol Use Disorders Identification Test (AUDIT) e Self-Reporting Questonnaire (SRQ-20), para avaliar o consumo de álcool e presença de transtorno mental, respectivamente. A pressão arterial foi medida com aparelho automático de braço validado. Foram realizadas três medidas e usada a média das duas últimas medidas. Realizaram-se ainda, medida do peso, altura, circunferência do pescoço, circunferência da cintura, avaliação de bioimpedância; glicemia, triglicérides e colesterol com medida capilar. Na análise bivariada, foi testada a associação entre hipertensos, separadamente, com os dois desfechos: consumo de bebidas alcoólicas e a presença de transtorno mental comum explorando especialmente, os aspectos relacionados à hipertensão arterial. Foi ajustada a regressão de Poisson com variância robusta, para ambos os desfechos, com modelagem em stepwise backward automatizado, tendo como critério de entrada, p<0,20 e de significância no modelo final, p0,05. Utilizou-se como estimativa, as razões de prevalência e respectivos intervalos de confiança de 95%. Resultados: A maioria dos participantes era do sexo feminino (57,8%), com 42,10 (16,74) anos, vivendo com companheiro (74,7%) e cerca de quatro filhos por família, baixo nível de escolaridade Analfabeto/Fundamental incompleto (41,1%) e renda até dois salários mínimos (85,0%). A prevalência de hipertensão arterial foi de 26,6%, tabagismo (20,4%) e ser sedentário/irregularmente ativo (52,8%). O consumo de bebida alcoólica foi de 40,2%, sendo 13,4% classificados como alto risco para dependência alcoólica, e maior na área rural em comparação à urbana (57,3% vs 22,2%) p<0,001. Destacam-se os seguintes aspectos do uso abusivo de álcool: sentimento de culpa/remorso (45,9%); amnésia repentina por não lembrar o ocorrido na noite em que bebeu (31,7%); além de machucar-se ou sentir-se prejudicado por causa da bebida (29,6%); preocupação por parte de parentes, amigos ou profissionais de saúde, que aconselharam o entrevistado a interromper o consumo (51,5%). Não houve associação entre a presença e consumo de bebida alcoólica (23% e 26%). Os indígenas com diagnóstico de hipertensão referida, faziam menos uso de bebida alcoólica (14,2%vs 85,8%, p=0,009), porém nas ocasiões em que bebiam, ingeriam maior quantidade, comparado com os que não referiram hipertensão [55,3(72,2) vs 33,3(62,2) gramas de Etanol p=0,008]. A prevalência de transtorno mental comum foi de 45,7%, com destaque para os seguintes itens: referência de dores de cabeça frequentes (69,5%), sentir-se nervoso, tenso ou preocupado (66,2%), ter se sentido triste ultimamente (56,0%), dormir mal (55,2%) e ter sensações desagradáveis no estômago (42,9%). Além disso, destaca-se que 7,3% referiram ideia de acabar com a própria vida e 4,2% sentiram-se incapazes de desempenhar papel útil. Após análise ajustada a razão de prevalência após análise ajustada (Razão de prevalência, IC-95%), verificou-se associação positiva entre ingestão de bebida alcoólica e sexo masculino (2,72, IC-2,12-3,48), tabagismo (1,29, IC-1,06-1,56) e morar na zona rural (2,09, IC-1,61-2,72). Porém, a ação foi protetora para idade (0,98, IC-0,98-0,99), consumo de alimentos in natura (0,97, IC-0,95-0,99), e ausência de dislipidemias (0,75, IC-0,62-0,9). Entre os que apresentaram transtorno mental comum, a hipertensão arterial identificada esteve presente em 30,3% e o consumo de álcool uma vez ao mês em 22,1%. Após a análise ajustada (Razão de prevalência, IC-95%) verificou-se associação positiva entre o transtorno mental comum e a zona de moradia urbana (1.25, IC-1,02-1,54), não sabia que tinham antecedentes para diabetes (1.56, IC-1,24-1,96) e a ingestão de bebida alcoólica (1.01, IC-1,00-1,02). Porém, foi ação protetora não ter antecedentes pessoais de cardiopatia (0.59, IC-0,48-0,73). Conclusão: Observou-se que a presença de hipertensão arterial, consumo de bebida alcoólica e de transtorno mental comum foram elevados nos indígenas da etnia Mura. Esses achados podem ser decorrentes da aproximação e convivência entre indígenas e não indígenas favorecendo mudanças culturais, especialmente de hábitos e estilos de vida, com aumento do risco de doenças crônicas não transmissíveis. / Background: The arterial hypertension has a multifactorial disorder, including unappropriated habits and lifestyle as the excessive consumption of alcoholic beverages that may increase the blood pressure. Additionally, the symptoms related to the common mental disorder may be also associated with the health status, producing even more damages to the hypertensive subjects. Thus, this study aimed to identify the association of arterial hypertension occurrence with alcoholic beverages consumption and presence of common mental disorder in Indigenous from Mura villages, who live in rural and urban zones. Casuistic and Methods: Its a cross-sectional investigation, with demographic base, conducted with 455 Mura Indigenous from Autazes, Amazon, Brazil. Through a semi-structured interview, we gathered data about sociodemographic and educational profile, lifestyle, clinical records, family antecedents. In this occasion, the Alcohol Use Disorders Identification Test (AUDIT) and the Self-Reporting Questionnaire (SRQ-20) were applied to assess respectively the alcohol consumption and the presence of common mental disorder. The blood pressure was measured with an arm automatic device, validated for this goal, being three measures taken and, from the two last of them, a mean was obtained. Furthermore, we gathered weight, height, neck circumference, waist circumference, bioimpedance, glycemia, triglycerides and cholesterol, capillary measure for the last ones. In the bivariate analysis, we analyzed the association between hypertensive persons and the both outcomes- the alcohol consumption and the presence of common mental disorder, emphasizing the issues hypertension-related issues. The Poison regression, with robust variance, was adjusted for both outcomes, with a modelling in automatized stepwise backward, being p<0,20 the entrance criteria and p<0,05 the significance level for the final model. As estimative, we used the odds ratios and their respective confidence intervals of 95%. Results: Most were females (57,8%), with mean age of 42,2(16,74) years, living with a partner (74,7%), with about four children per family, poor educational level- Illiterate/Incomplete Basic (41,1%) and income of up two minimum wages (85,0%). 26,6% of the sample had hypertension, 20,4% were smokers and 52,8% were sedentary/irregularly active. Alcohol consumption was of 40,2%, with 13,4% showed high risk for alcohol addiction, and the consumption was higher in rural area in comparison with the urban one (57,3% vs 22,2%) p<0,001. We emphasize the following aspects of alcohol abuse: feeling of guilty and remorse (45,9%); abrupt amnesia for not remembering what happened in the night that they had drunk (31,7%); feeling hurt or impaired due to the drink consumption (29,6%); concerns from relatives, friends or healthcare professionals who advised the interviewed to interrupt the consumption (51,5%). There was not association between presence and alcoholic beverages consumption (23% and 26%). Indigenous diagnosed with referred arterial hypertension drank less alcoholic beverages (14,2%vs 85,8% p=0,009), but, when they drank, they had a larger amount than those with referred hypertension [55,3(72,2) vs 33,3(62,2) grams of Ethanol p=0,008]. The common mental disorder was identified in 45,7% of the individuals, being highlighted the following items: reporting of frequent headaches (69,5%), feeling nervous, anxious or worried (66,2%), feeling sad in the last days (56,0%), sleeping badly (55,2%) and having upset stomach (42,9%). Additionally, 7.3% reported the idea of committing suicide, and 4,2% felt themselves unable to play a useful role. We verified positive association between alcoholic beverage consumption and male gender (2.72, CI-2,12-3,48); smoking (1.29, CI-1.06-1.56); and living in rural area (2.09, CI-1.61-2.72). However, the action was protective for the age (0.98, CI-0,98-0,99), intake of natural foods (0.97, CI-0,95-0,99), and absence of dyslipidemias (0.75, CI-0,62-0,9). Among those diagnosed with common mental disorder, the arterial hypertension was found in 30,3% and the alcohol consumption once a month in 22,1%. We observed a positive association of common mental disorder and: living in the urban area (1.25, CI-1,02-1,54); unknowing the antecedents for diabetes (1.56, CI-1,24-1,96); and the alcohol consumption (1.01,CI-1,00-1,02). However, the absence of personal background of heart diseases was not protective (0.59, CI-0,48-0,73). Conclusion: We observed that the presence of arterial hypertension, alcoholic beverages consumption and common mental disorder were high in the Mura ethnicity. This finding may be explained for the approach and interaction among Indigenous and non-Indigenous, which favors cultural changes, especially in habits and lifestyle, increasing the risk of non-transferable chronic diseases.

Estudos caracterizaram o envolvimento da PDI na modulação da geração de EROs pela Nox1 como moduladores da migração de células do músculo liso vascular (VSMC) mediados por fatores de crescimento derivados de plaqueta (PDGF). Outros estudos vêm demonstrando o envolvimento do fator de crescimento epidermal (EGFR) no remodelamento vascular, após a transativação via Angiotensina II. Entretanto o papel da PDI na ativação do EGFR via Nox1 na hipertensão arterial ainda permanece desconhecido. Objetivo foi caracterizar o papel da PDI na expressão de Nox1 dependente do EGFR durante o desenvolvimento da hipertensão arterial. Resultados demonstram um aumento da expressão de HB-EGF e ativação de ERK 1/2 na aorta de animais SHR com 8 semanas e 12 semanas de idade, e no plasma de animais SHR com 12 semanas. Ainda, a OvxPDI acarretou em um aumento na expressão gênica de Nox-1 tanto na OVXPDI quanto na forma OvxPDIMUT. Resultados mostram um novo papel da PDI na expressão gênica de Nox-1 via EGFR e a participação desta tiol oxido redutase na gênese da hipertensão arterial. / Studies characterizing the involvement of PDI in the modulation of ROS by Nox1 as modulators of cell migration of vascular smooth muscle (VSMC) mediated by growth factors derived from platelets (PDGF). Other studies have demonstrated the involvement of the epidermal growth factor receptor (EGFR) on vascular remodeling after transactivation via Angiotensin II. However the role of PDI in the activation of EGFR via Nox1 in hypertension remains unknown. Objective was to characterize the role of PDI in Nox1 dependent EGFR expression during the development of hypertension. Results show an increase of HB-EGF expression and ERK 1/2 activation in the aortic SHR at 8 weeks and 12 weeks of age, and plasma SHR at 12 weeks. Still, the OvxPDI resulted in an increase in gene expression of Nox-1 both in OVXPDI and in OvxPDIMUT way. Results show a new role of PDI in gene expression of Nox-1 via EGFR and the participation of this thiol reductase oxide in the pathogenesis of hypertension.

A homocisteína plasmática é considerada marcador de risco para doenças cardiovasculares e sua associação com a hipertensão arterial essencial parece ser importante no agravamento desta doença. O exercício físico tem mostrado eficácia na redução da pressão arterial e o ácido fólico suplementar a dieta como a melhor conduta para a redução da homocisteinemia. O objetivo deste trabalho foi verificar o efeito da suplementação de ácido fólico e/ou do exercício físico sobre as concentrações plasmáticas de homocisteína em hipertensos essenciais medicados. Para tanto foram estudados 69 hipertensos (57&#177;10 anos), sendo 22 do sexo masculino e 47 do sexo feminino, divididos em dois grupos: grupo 1 medicado com diurético e grupo 2 medicado sem diurético, sendo o tiazídico o diurético mais utilizado (80%). Foram realizadas avaliações médica, antropométrica, dietética, pressórica, bioquímica e o teste de aptidão cardiorrespiratória. Os indivíduos receberam suplementação com 500 &#181;g/dia de ácido fólico, em estudo do tipo cruzado, e foram submetidos a treinamento com exercícios físicos supervisionados, sendo reavaliados a cada dois meses até o final do estudo. Os grupos foram homogêneos em relação a todas as variáveis estudadas exceto a homocisteína plasmática que foi maior significativamente no grupo 1. Não houve diferença significativa entre os sexos para todas as variáveis estudadas. Os hipertensos eram em sua maioria (62%) não controlados e portadores de síndrome metabólica (77%). O exercício físico apresentou efeito benéfico na reclassificação dos hipertensos leves e moderados para a classe de limítrofes sem normalizar a pressão arterial. Não houve efeito do exercício na composição corporal e na homocisteinemia. A suplementação de ácido fólico reduziu a hiperhomocisteinemia em 11% no grupo 1 e 19% no grupo 2 frente a aumentos similares na folacemia. Em relação à pressão arterial houve normalização da homocisteinemia apenas nos hipertensos com pressão arterial normalizada. Os hipertensos limítrofes e leves apresentaram reclassificação da hiperhomocisteinemia limítrofe para moderada. A presença de diurético potencializou a normalização da pressão pelo exercício físico e indiretamente influenciou, nesses casos, a normalização da homocisteína. Entretanto, a maior redução das concentrações médias de homocisteína ocorreu coma oferta de ácido fólico na ausência de diurético. Desta forma, recomenda-se a adequação dietética do folato como adjuvante terapêutico da hipertensão arterial associadamente ao exercício físico e/ou medicamentos / The plasma homocysteine is considered to be a risk indicator for cardiovascular diseases and its association with essential hypertension seems to be important to the worsening of this disease. Physical exercises are efficient to reduce blood pressure and the dietary supplements of folic acid are considered the best way to decrease homocysteine. The aim of this study was investigate the effect of acid folic supplementation and physical exercises on plasmatic levels of homocysteine in essential hypertensive medicated individuals. In order to that, 69 hypertensive subjects were studied (22 men and 47 women) divided in two groups: group 1 medicated with diuretic and group 2 medicated without diuretic. Medical, anthropometrical, dietetic, blood pressure, biochemistry and cardio-respiratory capacity evaluations were performed. These individuals received 500 &#181;g/dia of folic acid supplementation in a cross-over design and were submitted to daily supervisioned physical exercise. They were evaluated every two months until the end of the study. The groups were similar for all variables except for the homocysteine which was significantly greater in the group 1. There were no difference for the gender to all variables. The high blood pressure was not controlled (62%) and 77% of the patients showed metabolic syndrome. The physical exercise showed benefit on the reclassification of slight and moderated hypertensives to border-line hypertension, however, it did not normalize the blood pressure. There were no effects on the body composition and on homocysteine values . Folic acid supplementation decreased 11% of hyperhomocysteinemia in the group 1 and 19% in group 2 face to similar increases in folate. Regarding to high blood pressure subjects the homocysteine normalization occurred only in hypertensive subjects with normalized blood pressure. The border and slightly hypertensive individuals had border-line hyperhomocysteine wich were reclassificated to moderated c1ass. The use of diuretic enhanced blood pressure normalization with the physical exercise and indirectly influenced the plasma homocysteine normalization. However the greater decreasing mean homocysteine concentration occurred with folic acid but in the diuretic absence. So we strong recommend an adequate folate intake as a terapheutical adjuvant to arterial hypertension treatments either with physical exercise and/or antihipertensive drugs.

Os objetivos desta pesquisa foram: compreender a perspectiva do profissional de saúde e do usuário hipertenso sobre a interação que ocorre entre eles no contexto da atenção em unidades públicas de saúde e analisar de que forma essa interação contribui para a não-adesão ao regime terapêutico. A metodologia aplicada para o desenvolvimento do estudo foi a Teoria Fundamentada nos Dados e o referencial teórico utilizado para a análise dos dados e interpretação dos resultados foi o Interacionismo Simbólico, além da literatura existente sobre o assunto. Ao todo, quinze profissionais de saúde e dez usuários fizeram parte da pesquisa. Ao final, foram encontradas seis categorias (duas delas, centrais) e outras subcategorias as quais, depois de um processo elaborado de comparações, relações e integração compuseram a proposição teórica que a autora fez sobre a interação entre o usuário e o profissional de saúde e da qual extraiu elementos para analisar a contribuição que essa interação tem para a não-adesão ao regime terapêutico. A autora concluiu que a interação, por ser pautada no modelo biomédico, centralizada no profissional de saúde, desigual, assimétrica e distanciada, tem elementos que podem estar contribuindo para a não- adesão do usuário ao regime terapêutico. Concluiu também que a principal ação que o profissional de saúde utiliza para promover a adesão do usuário ao regime terapêutico – a conscientização – tem sido ineficaz uma vez que se baseia no modelo tradicional de educação em saúde e no qual o usuário não é considerado como sujeito. Outra conclusão é a de que o usuário, por estar administrando o regime terapêutico à sua maneira, tem feito indicações ao profissional de saúde sobre sua forma de ver, entender e conviver com a hipertensão arterial e o regime terapêutico que nem sempre é congruente com o que o profissional de saúde quer e espera dele. Esta pesquisa aponta para a necessidade do profissional de saúde e outras instâncias políticas de decisão repensarem a interação profissional / usuário nos moldes que tem acontecido atualmente e para a necessidade de mudanças no modo de pensar e agir em relação ao usuário e com ele. / The aims of this research were to understand the perspective of the health professional and the hypertensive user about the interaction that occurs between them in the context of the service in health units and to analyze how this interaction contributes to the non-adherence to the therapeutic regime. The methodology applied for the development of the study was the Grounded Theory and the theoretical reference used for the analysis of the data and interpretation of the results was the Symbolic Interacionism, as well as existing literature on the subject. In all, fifteen health professionals and ten users were involved in the research. At the end, six categories were found (two of which were central) and other subcategories which, after an elaborated process of comparisons, relations and integration composed the theoretical proposal that the author made about the interaction between the user and the health professional and from which some elements were extracted in order to analyze the contribution that this interaction makes to the nonadherence to the therapeutic regime. The author concluded that the interaction, being based in the biomedical model, was centered in the health professional, was unequal, asymmetric and distant, and has elements that could be contributing to the user non-adherence to the therapeutic regime. It was also concluded that the main action that the health professional uses to make the user adhere to thetherapeutic regime – making the user aware of it – has been ineffective because it is based on the traditional model of health education in which the user is not considered individually. Another conclusion is that the user since he is managing the therapeutic regime in his own way has made indications to the health professional of his way of seeing, understanding and dealing with the arterial hypertension and the therapeutic regime that is not always congruent with what the health professional wants and expects of him. This research points to the necessity of the health professional and other policy-making forums to rethink the health professional/user interaction in the molds that have happened currently, and for the necessity of change in the way of thinking and of acting in relation to and with the user.

Le terme d’« hypertension artérielle pulmonaire » (HTAP) décrit une maladie vasculaire pulmonaire caractérisée par une augmentation progressive des pressions artérielles pulmonaires (PAP), définie par une PAP moyenne supérieure ou égale à 25 mmHg au repos et dont le principal symptôme est un essoufflement à l’effort. Un remodelage artériel pulmonaire intense conduisant à une obstruction des petits vaisseaux pulmonaires est responsable de la maladie. C’est une maladie rare mais néanmoins grave car pouvant aboutir à une insuffisance ventriculaire droite et entraîner le décès du patient.Le cadre général de notre étude est l’amélioration de la compréhension des mécanismes physiopathologiques de l’HTAP afin d’identifier de nouvelles cibles thérapeutiques potentielles. Nous nous sommes intéressés plus particulièrement au phénotype « pseudo-tumoral » des cellules musculaires lisses des artères pulmonaires (CML-AP) des patients atteints d’HTAP qui jouent un rôle primordial dans le remodelage vasculaire pulmonaire de l’HTAP et qui présentent des caractéristiques communes avec les cellules cancéreuses, notamment une hyper-prolifération, une résistance à l’apoptose, des désordres métaboliques et une instabilité génomique. Etant donné que la protéine p53, un des plus importants suppresseurs de tumeur, est largement décrite comme inactivée dans la plupart des cancers, nous avons émis l’hypothèse qu’elle pourrait également jouer un rôle important dans le développement de l’HTAP. Les résultats des études in vitro menées sur des CML-AP de patients atteints d'HTAP idiopathiques (HTAPi) versus des sujets contrôles semblent indiquer que la protéine p53 n’est pas altérée dans les CML-AP HTAPi. En effet, la séquence codante du gène TP53 ne présente pas de mutation dans les CML-AP HTAPi, les expressions génique et protéique de p53 (et de certaines de ses protéines cibles) ne semblent pas être différentes entre contrôles et HTAPi, ni à l’état basal ni en réponse à différents stress cellulaires inducteurs de p53 (étoposide et H2O2). Cependant, la régulation de p53 semble altérée puisque nous avons observé une augmentation du taux protéique de MDM2, principal régulateur de p53, dans les CML-AP HTAPi. Ce résultat peut être considéré comme une des caractéristiques « pseudo-tumorales » des CML-AP HTAPi mais également être un élément déterminant du mécanisme d’action de la Nutlin-3a, qui a montré des effets anti-prolifératifs accrus dans les CML-AP HTAPi.Dans des études in vivo menées chez le rat, la protéine p53 semble jouer un rôle dans l’initiation de la pathogénèse d’une HTAP. En effet, les taux protéiques pulmonaires de p53, de sa cible p21 et de son régulateur (mais également cible transcriptionnelle) MDM2 sont diminués lors de la première semaine dans un modèle d’induction d’HTAP par mono-injection de monocrotaline (MCT) chez le rat, au cours duquel la pathologie se développe à partir de la 2ème semaine. De plus, l’administration quotidienne à des rats d’un inhibiteur de l’activité transcriptionnelle de p53, le pifithrin-α (PFT), conduit au développement d’une HTAP en 14 jours, au même titre qu’une mono-injection de MCT, et aggrave l’HTAP induite par la MCT. Des effets pro-prolifératifs et anti-apoptotiques du PFT révélés sur des CML-AP indiquent que l’inhibition de l’activité transcriptionnelle de p53 est à l'origine d'une prolifération exagéree et une résistance à l'apoptose, deux composantes clés dans le remaniement vasculaire pulmonaire et le développement de l'HTAP.En conclusion, ces résultats mettent en évidence l’implication de l’inactivation de la voie de p53 lors de la phase initiatrice du développement de l’HTAP, alors qu’aux stades tardifs et sévères de la maladie, il semble il y avoir une normalisation de p53. En revanche, l’augmentation de l’expression de son principal régulateur MDM2 observée dans les CML-AP de patients HTAP semble être une cible thérapeutique potentiellement intéressante. / Pulmonary artery hypertension (PAH) is a severe pulmonary vascular disease characterized by a progressive increase of the pulmonary arterial pressure (PAP), defined by a mean PAP greater than or equal to 25 mmHg at rest. The main symptom is a shortness of breath. An intense pulmonary arterial remodeling that leads to an obstruction of the small pulmonary vessels is responsible of the disease. PAH is a rare but severe disease that develops into right ventricular cardiac failure leading to the patient's death.The general framework of our study was to improve the understanding of the pathophysiology of PAH in order to identify new potential therapeutic targets and improve the clinical management of patients. In particular, we were interested in the “cancer-like phenotype” of PAH patient pulmonary arterial smooth muscle cells (PA-SMCs). PA-SMCs play a key role in the pulmonary vascular remodeling of PAH. These cells share characteristics with cancerous cells, such as: exaggerated proliferation, apoptosis resistance, metabolic disorders and genomic instability. Owing to the growth-suppressive and pro-apoptotic functions of p53 protein and its inactivation largely described in cancer, we hypothesized that the p53 pathway could also be altered during PAH development in PA-SMCs.The results of in vitro studies on PA-SMCs of late stage patients with idiopathic PAH (iPAH) versus control patients suggest that the p53 protein nor pathway is not altered in iPAH PA-SMCs. Indeed, the coding sequence of the TP53 gene presented no mutations in iPAH PA-SMCs. Analysis of mRNA and protein levels of p53 and its target proteins showed no difference between controls and iPAH PA-SMCs, neither in a basal state or in response to various cellular stresses such as etoposide and H2O2. However, regulation of p53 may be altered in iPAH PA-SMCs as we observed an increase of the MDM2 (the main p53 regulator) protein level compared to control. This last result may be considered as a “cancer-like” characteristic of iPAH PA-SMCs and also be a determining factor in the mechanism of action of Nutlin-3a, which had more important anti-proliferative effects in iPAH PA-SMCs than in control cells.In vivo studies in rats revealed, however, that the p53 pathway may play a role in the initiation stage of PAH pathogenesis. Indeed, kinetics evaluation of p53 lung expression in the PAH model, induced by a single injection of monocrotaline (MCT), revealed a decrease in the p53 protein level during the first week, followed by a normalization by the second week. PAH symptoms are developed in MCT rats after two weeks. Similarly, the protein levels of p21, a p53 target, and MDM2, the major p53 regulator, and also a transcriptional target of p53, decreased during the first week in the MCT-PAH model. In addition, daily treatment in rats with an inhibitor of p53 transcriptional activity, pifithrin-α (PFT), led to the development of PAH in 14 days, similarly to MCT, and worsened the PAH induced by MCT. Pro-apoptotic and anti-proliferative effects of PFT on PA-SMCs indicate that inhibition of p53 transcriptional activity causes an excessive proliferation and an apoptosis resistance, which are two key components of the pulmonary vascular remodeling and development of human and experimental PAH.In conclusion, these results demonstrate the involvement of the p53 pathway inactivation in the initiation stage of PAH development, whereas in late and severe stages of disease, its role seems to be less implicated. In contrast, the increased expression of MDM2 observed in PA-SMCs of PAH patients may be a potential therapeutic target.

Evidências recentes sugerem que as doenças periodontais podem desempenhar um papel relevante na etiologia e patogênese de doenças cardiovasculares e hipertensão arterial. A resposta inflamatória, com conseqüente elevação de marcadores sistêmicos como proteína C-reativa, fibrinogênio e interleucina-6, e a disfunção endotelial, podem ser os responsáveis por essa associação. Alguns estudos têm relatado maiores níveis pressóricos, maior massa ventricular esquerda e disfunção endotelial em pacientes com doenças periodontais. Ao mesmo tempo, estudos clínicos vêm mostrando que a terapia periodontal pode levar à redução dos níveis plasmáticos dos marcadores de inflamação e redução do risco cardiovascular. O presente estudo teve como objetivo avaliar os efeitos da terapia periodontal não-cirúrgica em 26 pacientes (idade média de 53.68.0 anos) hipertensos refratários. Foram avaliados marcadores plasmáticos de inflamação (proteína C-reativa, fibrinogênio e interleucina-6), pressão arterial sistólica e diastólica, massa ventricular esquerda e rigidez arterial. A terapia periodontal foi eficaz na redução da média de todos os marcadores de risco cardiovascular avaliados. Os níveis de proteína C-reativa baixaram 0.7mg/dl 6 meses após a terapia periodontal, os de IL-6, 1.6pg/dl e os de fibrinogênio 55.3mg/dl (p<0.01). A pressão arterial sistólica apresentou redução média de 16.7mmHg e a diastólica de 9.6mmHg. A massa ventricular esquerda diminuiu em média 12.9g e a velocidade da onda de pulso, um marcador de rigidez arterial, e consequentemente de disfunção endotelial, apresentou redução de seus valores médios de 0.9m/s (p<0.01). Dessa forma, conclui-se que a terapia periodontal foi eficaz na redução dos níveis de proteína C-reativa, interleucina-6, fibrinogênio, pressão arterial, massa ventricular esquerda e rigidez arterial. / Recent evidences suggest that periodontal diseases may play a relevant role in the etiology and pathogenesis of cardiovascular diseases and hypertension. The inflammatory response, and the consequent elevation of systemic markers such as C-reactive protein, fibrinogen and interleukin-6, and endothelial dysfunction, may be responsible for this association. Some studies have reported higher blood pressure levels, left ventricle mass and endothelial dysfunction in patients presenting periodontal diseases. At the same time, clinical trials have been showing that periodontal therapy can lead to the reduction of plasmatic levels of inflammatory markers and reduction of the cardiovascular risk. The present study aims to evaluate the effects of non-surgical periodontal therapy in 26 patients (mean age: 53.68.0 years old) diagnosed as having refractory hypertension. The study measured plasmatic markers of inflammation (C-reactive protein, fibrinogen and interleukin-6), systolic and diastolic blood pressure, left ventricle mass and arterial stiffness. Periodontal therapy was effective in reducing all cardiovascular risk markers evaluated. The levels of C-reactive protein lowered 0.7mg/dl 6 months after periodontal therapy, the IL-6 levels, 1.6pg/dl and fibrinogen levels 55.3mg/dl (p<0.01). Systolic blood pressure lowered 16.7mmHg and diastolic 9.6mmHg (means). Left ventricle mass lowered 12.9g (means) and pulse wave velocity, a marker of arterial stiffness, and consequently endothelial dysfunction, presented reduction of 0.9m/s (means) (p<0.01). So, the study conclusion is that periodontal therapy was effective in reducing levels of C-reactive protein, interleukin-6, fibrinogen, blood pressure, left ventricle mass and arterial stiffness.

Made available in DSpace on 2014-06-11T19:30:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-25Bitstream added on 2014-06-13T21:01:31Z : No. of bitstreams: 1 fernandes_ra_dr_rcla.pdf: 1297724 bytes, checksum: 896dd66dcf9341e251f414b66fbe846a (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: A prevalência da prática regular de atividades físicas na população adulta brasileira ainda é desconhecida, principalmente em cidades do interior dificultando assim a elaboração de campanhas efetivas na promoção de sua prática. Objetivo: Portanto, o objetivo deste trabalho foi analisar, em adultos de ambos os sexos no Estado de São Paulo, a prevalência da prática regular de atividades físicas e suas associações com as doenças cardio-metabólicas. Métodos: Por meio de amostragem aleatória em diferentes estágios, uma amostra de 2720 adultos (idade > 18 anos) foi selecionada em oito cidades do Estado de São Paulo. As entrevistas foram feitas nos domicílios dos entrevistados através de questionários sobre: (i) Atividade física atual no lazer (fisicamente ativo se ≥180min/sem de atividades moderadas ou vigorosas a mais de 4 meses); (ii) Barreiras pessoais; (iii) Atividade física na infância e adolescência; (iv) Doenças e excesso de peso; (v) Informações gerais (sexo, escolaridade e idade). O teste qui-quadrado analisou associações entre os dados categóricos e a regressão logística analisou a magnitude das mesmas. Resultados: No lazer, homens foram mais ativos do que as mulheres (p= 0,001), bem como, grupos com maior escolaridade (p= 0,007) e menor idade (p= 0,002) foram mais ativos. Moradores da capital foram menos ativos do que moradores do litoral e interior do estado (p= 0,001). Tanto na capital, como no interior e litoral, quanto maior o número de barreiras pessoais, menor a prática de atividades no lazer (p= 0,001 para todos). Adultos que praticaram atividades esportivas na infância e adolescência apresentaram 1,6 vezes mais chances de serem ativos no lazer (p= 0,001). Além disso, indivíduos que foram ativos ao longo da vida apresentaram 45% (p= 0,013), 35% (p= 0,010) e 49% (p= 0,011) menos chance de relatar hipertensão arterial... / Background: Physical activity level in Brazilian adults is unknown, mainly in non-capital cities and this absence of data difficult the implementation of effective promotion programs. Objectives: To analyze, in adults of both genders living in Sao Paul State, the physical activity level and its associations with some diseases. Methods: A sample of 2720 adults has been selected in eight cities of the Sao Paulo State through a multistage random process. Questionnaires were applied through home interviews: (i) current physical activity (physically active: ≥180min/wk of either moderate or vigorous activities for at lest 4 months before the interview); (ii) Personal barriers; (iii) Early physical activity; (iv) Diseases and overweight; (v) general information (gender, schooling and age). Chi-square test analyzed associations among categorical data and logistic regression indicated the magnitude of it. Results: In leisure time, men were more physically active than women (p= 0.001), as well as, groups of higher schooling (p= 0.007) and lower age (p= 0.002). People living in Capital reported lower physical activity practice than those one from coast and non-capital cities (p= 0.001). In all cities, higher number of personal barriers was associated with lower leisure time physical activity (p= 0.001 for all). Adults engaged in sport activities during childhood and adolescence had 1.6 more likely to be active in leisure time (p= 0.001). Moreover, persons persistently active through life had 45% (p= 0.013), 35% (p= 0.010) and 49% (p= 0.011) less likely to report arterial hypertension, dyslipidemia and obesity, respectively. Area residents of places with higher number of public parks were more physically actives (p= 0.005), but not in the Capital (p= 0.982). Conclusions: physical activity level is higher in coast and non-capital cities, as well as, in the Capital there were more personal... (Complete abstract click electronic access below)

Orientador: Angelina Zanesco / Banca: Maria Claudia Costa Irigoyen / Banca: Katia de Angelis / Banca: Henrique Luiz Monteiro / Banca: Rodolfo Franco Puttini / Resumo: Introdução: A prevalência da prática regular de atividades físicas na população adulta brasileira ainda é desconhecida, principalmente em cidades do interior dificultando assim a elaboração de campanhas efetivas na promoção de sua prática. Objetivo: Portanto, o objetivo deste trabalho foi analisar, em adultos de ambos os sexos no Estado de São Paulo, a prevalência da prática regular de atividades físicas e suas associações com as doenças cardio-metabólicas. Métodos: Por meio de amostragem aleatória em diferentes estágios, uma amostra de 2720 adultos (idade > 18 anos) foi selecionada em oito cidades do Estado de São Paulo. As entrevistas foram feitas nos domicílios dos entrevistados através de questionários sobre: (i) Atividade física atual no lazer (fisicamente ativo se ≥180min/sem de atividades moderadas ou vigorosas a mais de 4 meses); (ii) Barreiras pessoais; (iii) Atividade física na infância e adolescência; (iv) Doenças e excesso de peso; (v) Informações gerais (sexo, escolaridade e idade). O teste qui-quadrado analisou associações entre os dados categóricos e a regressão logística analisou a magnitude das mesmas. Resultados: No lazer, homens foram mais ativos do que as mulheres (p= 0,001), bem como, grupos com maior escolaridade (p= 0,007) e menor idade (p= 0,002) foram mais ativos. Moradores da capital foram menos ativos do que moradores do litoral e interior do estado (p= 0,001). Tanto na capital, como no interior e litoral, quanto maior o número de barreiras pessoais, menor a prática de atividades no lazer (p= 0,001 para todos). Adultos que praticaram atividades esportivas na infância e adolescência apresentaram 1,6 vezes mais chances de serem ativos no lazer (p= 0,001). Além disso, indivíduos que foram ativos ao longo da vida apresentaram 45% (p= 0,013), 35% (p= 0,010) e 49% (p= 0,011) menos chance de relatar hipertensão arterial... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Physical activity level in Brazilian adults is unknown, mainly in non-capital cities and this absence of data difficult the implementation of effective promotion programs. Objectives: To analyze, in adults of both genders living in Sao Paul State, the physical activity level and its associations with some diseases. Methods: A sample of 2720 adults has been selected in eight cities of the Sao Paulo State through a multistage random process. Questionnaires were applied through home interviews: (i) current physical activity (physically active: ≥180min/wk of either moderate or vigorous activities for at lest 4 months before the interview); (ii) Personal barriers; (iii) Early physical activity; (iv) Diseases and overweight; (v) general information (gender, schooling and age). Chi-square test analyzed associations among categorical data and logistic regression indicated the magnitude of it. Results: In leisure time, men were more physically active than women (p= 0.001), as well as, groups of higher schooling (p= 0.007) and lower age (p= 0.002). People living in Capital reported lower physical activity practice than those one from coast and non-capital cities (p= 0.001). In all cities, higher number of personal barriers was associated with lower leisure time physical activity (p= 0.001 for all). Adults engaged in sport activities during childhood and adolescence had 1.6 more likely to be active in leisure time (p= 0.001). Moreover, persons persistently active through life had 45% (p= 0.013), 35% (p= 0.010) and 49% (p= 0.011) less likely to report arterial hypertension, dyslipidemia and obesity, respectively. Area residents of places with higher number of public parks were more physically actives (p= 0.005), but not in the Capital (p= 0.982). Conclusions: physical activity level is higher in coast and non-capital cities, as well as, in the Capital there were more personal... (Complete abstract click electronic access below) / Doutor