<p>During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world.</p><p>The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality.</p><p>The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM).</p><p>The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. </p><p>It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. </p><p>The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. </p><p>A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.</p><p>In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.</p>

During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world. The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality. The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM). The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture. It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI. The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors. In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 86-91). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

The literature reports beneficial effects of aminoguanidine and its derivatives on the cardiovascular system. This work utilized strategies of Medicinal Chemistry, such as molecular hybridization and bio-ossification, for the synthesis of 14 aromatic aminoguanidine derivatives (DAGs), in order to investigate effective, safe and less effective adverse therapeutic alternatives for the treatment of hypertension. After pharmacological screening with the 14 DAGs, in order to select the most efficient derivative with respect to its cytotoxic activity and vasorelaxant effect, the work follows with the characterization of the cardiovascular effects induced by LQM01 in Spontaneously Hypertensive Rats (SHR), Through experimental approaches in vitro and in vivo, using the method of preparations with superior mesenteric artery isolated from rat and direct and indirect blood pressure measurement, respectively. The LQM01 derivative showed very low cytotoxic activity in MTT assays with reduced cell growth only at high concentrations. The derivative 01 also promoted a vasorelaxant effect similar to the Guanabenzo antihypertensive drug, a positive control, in rings pre-contracted with FEN, independently of endothelium. The observed effect showed a significant deviation of the response curve from LQM01 to the right, in precontracted FEN rings, in the presence of the 5 mM TEA blocker, a non-selective blocker of the K+ channels of the 4-AP blocker, a blocker (1mM) and TEA 1mM, a selective BKCa blocker, thus suggesting the participation of KV, BKCa in the vasorelaxation effect induced by LQM01. As in the depolarizing solution of KCl 80mM vasorelaxation was reduced, suggesting the inhibition of Ca2+ influx through the VOCCs, such hypothesis is justified by the attenuation of the CaCl2-induced contractions in the depolarizing solution nominally without Ca+2. In non-anesthetized SHR rats, i.v. in bolus administration of LQM01 induced dose-dependent hypotension with a more significant hypotensive effect at doses of 5 and 10 mg/kg, accompanied by an intense bradycardic effect. However, after CNS depression in the group of animals anesthetized with sodium thiopental, both the hypotensive and bradycardic responses induced by the derivative were attenuated or virtually abolished, respectively. In addition, the LMQ01 derivative was able to promote antihypertensive activity, at doses of 5 and 10 mg/kg, by its orogastric administration from the second hour, but at the fourth and sixth hour only at the highest dose, without Significant changes in HR at both doses. Conclusion: The data suggest that LQM01 promotes vasodilator effect through channel stimulation for K+, Kv and BKCa, besides inhibiting Ca2+ influx, possibly through blocking VOCCs, as well as promoting hypotensive, bradycardic and anti- Hypertensive, which may be due to a direct action of the substance on the MLV, inducing vasorelaxation and consequent reduction of peripheral vascular resistance, contributing to its hypotensive action, but may also have an inhibitory influence on the neural control system that acts on the cardiovascular system. / Conselho Nacional de Desenvolvimento Científico e Tecnológico / A Literatura relata efeitos benéficos da aminoguanidína e seus derivados sobre o sistemacardiovascular. Este trabalho utilizou-se de estratégias da Química Medicinal, como hibridação molecular e bioisosterismo, para síntese de 14 derivados aminoguanidínicos (DAGs) aromáticos, com o propósito de pesquisar alternativas terapêuticas eficazes, seguras e com menos efeitos adversos para o tratamento da hipertensão. Após triagem farmacológica com os 14 DAGs, a fim de selecionar o derivado com melhor eficácia, no que se refere a sua atividade citotóxica e efeito vasorelaxante, o trabalho segue com a caracterização dos efeitos cardiovasculares induzidos por LQM01 em Ratos Espontaneamente Hipertensos (SHR), através de abordagens experimentais in vitro e in vivo, utilizando o método de preparações com artéria mesentérica superior isolada de rato e medida direta e indireta pressão arterial, respectivamente. O derivado LQM01 apresentou em ensaios de MTT, atividade citotóxica muito baixa, com redução do crescimento celular apenas em altas concentrações. O derivado 01 também promoveu efeito vasorelaxante semelhante ao fármaco anti-hipertensivo Guanabenzo, controle positivo, em anéis pré-contraídos com FEN, de maneira independente de endotélio. O efeito observado apresentou um desvio significativo da curva-concentração resposta de LQM01 para direita, em anéis pré-contraídos com FEN, na presença do bloqueador TEA 5 mM, um bloqueador não-seletivo dos canais de K+ do bloqueador 4-AP, um bloqueador seletivo dos KV (1mM) e TEA 1mM, bloqueador seletivo dos BKCa sugerindo assim a participação dos KV , BKCa no efeito vasorelaxante induzido por LQM01. Assim como, em solução despolarizante de KCl80mM o vasorelaxamento mostrou-se reduzido, sugerindo a inibição do influxo de Ca2+ através dos VOCCs, tal hipótese é justificada pela atenuação das contrações induzidas por CaCl2 em solução despolarizante nominalmente sem Ca+2. Em ratos SHR não-anestesiados, a administração i.v. in bolus de LQM01 induziu hipotensão, de maneira independente de dose, com efeito hipotensor mais significativo nas doses de 5 e 10 mg/kg, acompanhado de efeito bradicárdico intenso. No entanto, após depressão do SNC no grupo de animais anestesiados com tiopental sódico, tanto a resposta hipotensora quanto a bradicárdica induzida pelo derivado foi atenuada ou praticamente abolida, respectivamente. Além disto, o derivado LMQ01 foi capaz de promover atividade anti-hipertensiva, nas doses de 5 e 10 mg/kg, a por meio de sua administração orogástrica a partir da segunda hora, porém na quarta e sexta hora apenas na maior dose, sem promover alterações significativas sobre a FC, em ambas as doses. Em conclusão: Os dados sugerem que o LQM01 promove efeito vasodilatador através da estimulação de canais para K+, Kv e BKCa, além de inibir o influxo de Ca2+, possivelmente através do bloqueio dos VOCCs, bem como, promover efeito hipotensor, bradicárdico e anti-hipertensivo, que pode ser devido a uma ação direta da substância sobre a MLV, induzindo vasorelaxamento e consequente redução da resistência vascular periférica, contribuindo para sua ação hipotensora, como também pode ter influência inibitória sobre o sistema de controle neural que atua sobre o sistema cardiovascular.

Introdução: As doenças cardiovasculares são atualmente a principal causa de mortalidade no país e também o conjunto de doenças que provoca o maior gasto no sistema de saúde. Dentre elas, há uma que merece especial atenção por estar vinculada a diversas origens e ser fator de agravamento para outras patologias: a hipertensão arterial. O modelo assistencial vigente caracteriza-se por ações curativas, pelo atendimento ao paciente com patologia já instalada e visão extremamente limitada em especificidades dos problemas. O Programa de Saúde da Família propõe um modo diferente de atendimento, estruturada no atendimento ambulatorial contínuo e integral, se valendo da interação com a comunidade o que permite ações mais efetivas na promoção da saúde. A presença de um programa de atenção farmacêutica no PSF promove um maior trânsito, riqueza e percepção de informações a respeito de medicamentos, fazendo com que a terapia medicamentosa seja mais efetiva, com a promoção do uso correto. Objetivos: Desenvolver uma metodologia que permita identificar e analisar práticas terapêuticas medicamentosas anti-hipertensivas (Momento terapêutico ? MT). Estimar resultados e tendências na evolução da pressão arterial dos pacientes hipertensos acompanhados pelo NSF-III. Estimar o nível de adesão ao tratamento anti-hipertensivo e a influência desse fator no resultado terapêutico dos pacientes. Casuística e Métodos: População - Indivíduos cadastrados no Núcleo de Saúde da Família III (NSF-III) do PSF de Ribeirão Preto, com diagnóstico de hipertensão arterial e acompanhamento da patologia realizado no referido núcleo. Amostra: prontuários de 73 pacientes. Métodos - Foram coletados dados retrospectivos dos prontuários dos indivíduos, relativos ao período de 1.º de julho de 2001 a 30 de junho de 2005. Foram avaliados ?Conduta Diagnóstica? e os valores de pressão arterial. Resultados: Observou-se a redução de MT nos quais nenhum anti-hipertensivos (AH) foi utilizado, redução no uso de um AH isoladamente e aumento no número médio de AH por MT anos após ano (1,35 no Ano 1 até 1,89 no Ano 4). Analisando-se o percentual de MT de acordo com a classe de AH envolvida, verificou-se a predominância de prescrição da classe dos IECA (58,8%), seguida pelos diuréticos (54,4%) e BBloq e BloqCa em proporções próximas (19% e 18,2%, respectivamente). Foram encontradas indicações de uso irregular da medicação nos prontuários de 35 (48%) pacientes. O percentual médio de pacientes com controle de PA adequado foi de 34,2% no geral, 42.1% nos pacientes Aderentes e 25,7% nos Não Aderentes. Conclusões: A metodologia dos momentos terapêuticos se mostrou adequada na caracterização do padrão de prescrição do NSF-III, que segue as recomendações de tratamento de hipertensão baseada nos consensos, ou seja, a terapêutica medicamentosa praticada tende a ser racional. A maioria dos pacientes do PSF que faz acompanhamento em hipertensão arterial apresenta valores de pressão arterial fora dos limites internacionalmente estabelecidos. O presente trabalho também permitiu demonstrar que o problema de adesão ao tratamento no NSF-III é similar ao que já foi descrito na literatura mas a tendência a indiferenciação entre os grupos de pacientes aderentes e não aderentes indica que abordagem do programa tem conseguido resultados positivos / Introduction: Cardiovascular diseases are the currently leading cause of mortality in Brazil and also the set of illnesses that is the largest expense in health system. Amongst them, there is one that deserves special attention for being tied the diverse origins and to be factor of aggravation for other pathologies: hypertension. The actual model of care is characterized for curative actions and vision extremely limited in specificities of the problems. The Family Health Care Program (FHCP) considers a different way of care, structured in continuous and integral ambulatory care, considering the interaction with community as crucial for more effective actions on health promotion. The presence of a pharmaceutical care program in the FHCP promotes a better flow, quality, and perception of information regarding medicines, making drug therapy more effective with the promotion of the correct use. Objectives: To develop a methodology that allows to identify and analyze therapeutical pratices of antihypertensive drugs (Therapeutic Moment - TM). Esteem results and trends in the evolution of the blood pressure (BP) of the hypertensive patients followed by the NFHCIII. Esteem the level of adherence to the hypertension treatment and the influence of this factor in the therapeutic result of the patients. Casuistry and Methods: Population - Individuals registered in the Nucleus of Family Health Care III (NFHC-III) of the FHCP of Ribeirão Preto, with diagnosis of hypertension and accompaniment of the pathology. Sample: medical records of 73 patients. Methods - Data had been retrospectively collected relative to the period of 1.º of July of 2001 to 30 of June of 2005. Results: It was observed TM reduction in which no antihypertensives (AH) were used, reduction in the use of one single AH and increase in the average number of AH for TM (1,35 in Year 1 up to 1,89 in Year 4). Analyzing the percentage of TM in accordance with the class of AH involved, verified it predominance of prescriptions on the class of ACE (58.8%), followed for diuretics (54.4%), with betablockers and calcium channel blockers in next (19% and 18.2%, respectively). Indications of irregular use of medication in medical records of 35 (48%) patient had been found. Average percentage of the 73 patients with adequate control of BP was of 34,2%, 42,1% in the Adherent group of patients and 25.7% in Not Adherent. Conclusions: The methodology of therapeutic moments showed adequate results in the characterization of the practices of AH prescribing in the NFHC-III. This health care facility follows the recommendations of treatment of hypertension based on the Brazilian guidelines, suggesting that the drug practices tends to be rational. The majority of the patients of the NFHC-III that makes accompaniment in hypertension present values of blood pressure above of the limits internationally established. The present work also demonstrate that the problem of adherence to the treatment in the NFHC-III is similar of the already described in literature but trends of BP reduction values between the groups of adherent and not adherent patients indicates the approach of the program has obtained positive results

INTRODUÇÃO: A hipertensão é um importante problema de saúde pública e os estudos de Custo-Efetividade (C/E) do tratamento antihipertensivo são raros no Brasil. OBJETIVO: Realizar análise farmacoeconômica retrospectiva do tipo C/E do tratamento medicamentoso em hipertensos. MATERIAL E MÉTODOS: Foi analisado o custo (C) dos medicamentos anti-hipertensivos, do número de visitas médicas não programadas e do tratamento dos efeitos adversos e a efetividade (E) medida pela redução média da pressão arterial em mm Hg ao término de estudo sobre eficácia do tratamento Tradicional iniciado com hidroclorotiazida e atenolol comparado ao tratamento Atual iniciado com losartan e anlodipino, administrados aleatoriamente durante 12 meses a hipertensos sem outras doenças concomitantes pertencentes ao estágios 1 e 2 (grupo HT1-2 = 140 menor ou igual PAS < 180 e 90 menor ou igual PAD < 110 mm Hg) e ao estágio 3 (grupo HT3 = PAS > 180 e PAD > 110 mm Hg). RESULTADOS: A razão C/E (R$/mm Hg) no grupo HT1-2 (n = 231) para PAS/PAD dos tratamentos Atual e Tradicional foi de 112,52 ± 395,28 / 181,26 ± 358,91 e 43,05 ± 50,73 / 80,51 ± 108,31 (p < 0,05) ao passo que no grupo HT3 (n = 132) foi de 115,12 ± 254,87 / 108,14 ± 82,56 e 218,59 ± 891,93 / 173,97 ± 447,23 (p > 0,05). CONCLUSÃO: O tratamento Tradicional foi custo-efetivo em relação ao Atual nos hipertensos estágios 1 e 2. Por outro lado, nos hipertensos estágio 3 não houve diferença na razão C/E entre os tratamentos. Estes resultados foram confirmados quando foi utilizado o menor preço de aquisição dos medicamentos e quando foram considerados somente os pacientes que atingiram o controle da pressão arterial ao final do estudo. / INTRODUCTION: Hypertension is an important public health problem and Cost-Effectiveness (C/E) studies of antihypertensive drug treatment are uncommon in Brazil. OBJECTIVE: To perform a cost-effectiveness (C/E) ratio retrospective pharmacoeconomic analysis of drug treatment in hypertensive patients. MATERIAL AND METHODS: Antihypertensive medication cost (C) was analysed, along with the number of non-scheduled medical visits, treatment of adverse effects, and effectiveness (E) based on the average reduction of arterial blood pressure measured in mm Hg at the end of the study comparing the efficacy of a Traditional Treatment with hydrochlorothiazide and atenolol versus Current Treatment using losartan and amlodipine, administered at random for 12 months to hypertensive patients with no other simultaneous diseases and presenting disease stage 1 and 2 (HT1-2 Group = 140 < or = SBP < 180 and < or = 90 DBP < 110mmHg) and stage 3 (HT3 Group = SBP maior or = 180 and DBP > or = 110mmHg). RESULTS: The C/E ratio (R$/mmHg) in the HT1-2 Group (n=231), based on SBP/DBP, for Current and Traditional Treatments was 112.52 ± 395.28 / 181.26 ± 358.91 and 43.05 ± 50.73 / 80.51 ± 18.31 (p < 0.05), while in the HT3 Group (n=132), 115.12 ± 254.87 / 108.14 ± 82.56 and 218.59 ± 891.93 / 173.97 ± 447.23 (p>0.05). CONCLUSION: Traditional treatment was more cost-effective compared to the Current therapy in hypertensive patients with disease stages 1 and 2. On the other hand, in hypertensive patients with disease stage 3 there was no difference in C/E ratio between the treatment regimens. These results were confirmed by using the lowest purchase price of medication and by considering only patients that reached control of their blood pressures at the end of the study.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-11T20:01:58Z No. of bitstreams: 1 webertonreisdocarmo.pdf: 7569925 bytes, checksum: d21c1add8559c40e497cf970e0833679 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-13T16:38:18Z (GMT) No. of bitstreams: 1 webertonreisdocarmo.pdf: 7569925 bytes, checksum: d21c1add8559c40e497cf970e0833679 (MD5) / Made available in DSpace on 2016-07-13T16:38:18Z (GMT). No. of bitstreams: 1 webertonreisdocarmo.pdf: 7569925 bytes, checksum: d21c1add8559c40e497cf970e0833679 (MD5) Previous issue date: 2012-02-27 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A hipertensão arterial é uma doença que acomete milhões de pessoas no mundo todo, por esse motivo a classe de médicos cardiologistas na publicação da V Diretrizes Brasileiras de Hipertensão Arterial ressaltou a importância de não se obter medicamentos anti-hipertensivos via farmácias de manipulação. De acordo com o que foi discutido, isso se deve a inexistência de informações adequadas de controle de qualidade, bioequivalência e/ou interação química dos compostos. Os fármacos utilizados no tratamento da hipertensão são administrados oralmente na forma sólida, podendo, portanto, cristalizar-se em diversas formas cristalinas, fenômeno este conhecido como polimorfismo. O polimorfismo em fármacos é um tema de grande interesse para a comunidade cientifica e apresenta um grande desafio para as indústrias farmacêuticas, uma vez que alterações no arranjo cristalino podem alterar as propriedades físico-químicas dos fármacos, e consequentemente afetar o desenvolvimento, a segurança e a eficácia de um medicamento. A principal técnica de caracterização do polimorfismo é a difração de raios X, cuja principal vantagem em relação às outras técnicas consiste na habilidade de diferenciar de maneira inequívoca uma fase cristalina da outra, mesmo que essa possua a mesma composição. Devido a todos os pontos levantados, nesse trabalho realizou-se a identificação e a quantificação de fases cristalinas dos fármacos anti-hipertensivos, Losartana, Clortalidona e Hidroclorotiazida que são disponibilizados às farmácias de manipulação da cidade de Juiz de Fora, denominadas de A e B. Realizou-se também a quantificação de fases em associações dos mesmos. Para esses propósitos as técnicas utilizadas foram espectroscopia vibracional Raman, análise termogravimétrica (TG) e calorimetria exploratória diferencial (DSC), análise elementar de carbono, hidrogênio, nitrogênio e a difração de raios X por policristais. Os resultados mostraram que para os diuréticos (Clortalidona e Hidroclorotiazida) apenas uma fase cristalina foi encontrada nas amostras, porém para a Losartana foram observadas as fases ortorrômbica e monoclínica. A análise de fases indicou que a técnica pode ser utilizada na quantificação de associação de medicamentos. / Hypertension is one of the most prevalent diseases worldwide affecting millions of people, for this reason the cardiologists in the publication of the V Brazilian Guidelines on Hypertension emphasized the importance of not buying antihypertensive medications through manipulation pharmacies. According to what was discussed, this is due to a lack of adequate information quality control, bioequivalence and / or chemical interaction of the compounds. The drugs used to treat hypertension are administered orally in solid form and therefore can crystallize in different crystalline forms, a phenomenon known as polymorphism. Polymorphism in drugs is a topic of great interest to the scientific community and presents a great challenge for the pharmaceutical industry, since changes in the crystalline arrangement can change the physicochemical properties of drugs, and consequently affect the development, security and effectiveness of a drug. The main technique for polymorphism characterization is the X-ray diffraction, whose main advantage over other techniques is the ability to differentiate unequivocally one of the other crystalline phases, even though this has the same composition. Based on aforementioned points, in this work was carried out the identification and quantification of crystalline phases of antihypertensive drugs, Losartan, Hydrochlorothiazide and Chlorthalidone that are available to manipulation pharmacies in Juiz de Fora city, named A and B. There was also the quantification of phases in the same associations. For these purposes the techniques used were Raman vibrational spectroscopy, thermogravimetric analysis (TG) and differential scanning calorimetry (DSC), elemental analysis of carbon, hydrogen and nitrogen, and X-ray powder diffraction. The results showed that for diuretics (Hydrochlorothiazide and Chlorthalidone) only one crystalline phase was found in the samples, but for Losartan were observed orthorhombic and monoclinic phases. The phase analysis indicated that this technique can be used in quantifying drug combination.

Orientador: Cláudio Chrysostomo Werneck / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T04:57:03Z (GMT). No. of bitstreams: 1 Nery-Diez_AnaClaudiaCoelho_D.pdf: 21192177 bytes, checksum: 572bd54be1e7496c1fd325e94812ecc1 (MD5) Previous issue date: 2013 / Resumo: As mutações no gene da fibrilina-1, presente na fibra elástica, estão relacionadas à síndrome de Marfan, doença genética autossômica dominante. Acredita-se que a maioria dos seus sintomas esteja relacionada a uma hiper-ativação do fator TGF-?. Quando camundongos modelo para síndrome são tratados com losartan apresentam uma melhora significativa nos sinais clínicos. Assim, neste estudo, investigamos o papel de fibrilina-1 na análise de trombose arterial em modelos de camundongos para a síndrome de Marfan (Fbn1mg?/+). Foram analisados a formação de trombos, os níveis de plaquetas, APTT, PT e TT, agregação e adesão plaquetária, parâmetros hemodinâmicos, níveis de TGF-?, atividade das MMPs, bem como a morfologia das plaquetas, das fibras elásticas e dos trombos. Foi observado que os animais Fbn1mg?/+ necessitam de cerca de 120±21,07 minutos para formarem o trombo, enquanto os animais selvagens precisam de 58±7,16 minutos. Mas, quando os animais Fbn1mg?/+ foram tratados com anti-hipertensivos losartan e captopril, ocorreu uma recuperação no tempo de formação do trombo, com redução de 57,5% e 67,5% no tempo, respectivamente. Além disso, constatou-se que os animais Fbn1mg?/+ apresentam um aumento na atividade das MMPs e TGF-? ativos, quando tratados com os anti-hipertensivos, houve uma diminuição apenas na atividade das MMPs. Ademais, não foi verificada diferença significativa entre todos os outros parâmetros analisados. Este estudo sugere que, de alguma forma, as drogas interferem na remodelação da matriz elástica, devido a uma diminuição da atividade das metaloproteinases de matriz e, consequentemente, leva á recuperação na formação do trombo / Abstract: Recent works show that an increased activation of the TGF-? is associated with most of the symptoms of the Marfan syndrome. Studies using mouse models of Marfan treated with losartan have been shown to prevent the degradation of the elastic matrix. Other investigators suggest that the metalloproteinases and the noncanonical ERK signaling are involved in the breakdown of the elastic fiber, which results in the aneurysm. In this study we investigated the role of fibrillin-1 in the arterial thrombosis model using mouse models of Marfan. We analyzed thrombus formation, platelet levels, APTT, PT and TT time, hemodynamic parameter, TGF-? levels, MMP activity as well as platelets, elastic fibers morphology and thrombus. This study demonstrated that Fbn1mg?/+ mice take about 120±21,07 minutes for the thrombus to be formed when compared with wild type, 58±7,16. When these Fbn1mg?/+ mice were treated with antihypertensive losartan and captopril the time taken for the thrombus formation was reduced in 57,5% and 67,5%, respectively. The activity of metalloproteinases and activity TGF-? was increased in the Fbn1mg?/+, however no significant difference between the hemodynamic parameters, levels of totals TGF-?, morphological platelets, elastic fiber and thrombus were observed. Finally, the results suggested that fibrillin-1 interferes with this process and antihypertensive affect the physiology of Fbn1mg?/+ mice. This study suggested that somehow drugs interfere with elastic matrix remodeling due to a decrease in the activity of matrix metalloproteinases which results in the recovery time of thrombus formation / Doutorado / Bioquimica / Doutora em Biologia Funcional e Molecular

Abstract The aim of the present study was to describe the effects of different types of cold exposures on blood pressure (BP) and heart rate (HR) and to test how these cold-induced effects are modulated by antihypertensive drugs representing different kind of mechanisms of action. The tested drugs represented the following antihypertensive drug subgroups: metoprolol from beta-blocking agents, carvedilol from alfa- and beta-blocking agents, lisinopril from angiotensin converting enzyme inhibitors, eprosartan from angiotensin II antagonists, amlodipine from calcium channel blockers and hydrochlorothiazide from diuretics. The main outcome measures were the levels and changes in systolic (SBP) and diastolic blood pressure (DBP) and HR before, during and after cold exposure. The normotensive and mildly hypertensive subjects were exposed either to –15°C for 15 minutes (with winter clothing), 5°C for 45 minutes (minimal clothing) or to a cold pressor test (CPT). Before measurements at –15°C, metoprolol, carvedilol, lisinopril, eprosartan, hydrochlorothiazide or placebo were given for a week in a double-blind and crossover manner. In one test procedure (5°C and CPT) the test subjects ingested amlodipine for three days or were without drug ingestion before the tests in a crossover manner. Both SBP and DBP were markedly increased by all types of cold exposure. Cold-induced rises of SBP/DBP were higher during the exposure to 5°C and –15°C (19–35/20–24 mmHg) than during CPT (13/16 mmHg). Metoprolol, carvedilol, lisinopril, eprosartan and amlodipine decreased the level of BP during the exposure to 5°C and –15°C compared to placebo or no drug. The antihypertensive drugs, with dosages used in this study, did not affect the cold-induced rise of BP compared to no drug or placebo. HR increased during CPT, but decreased during exposure to 5°C and –15°C. Metoprolol and carvedilol decreased HR during exposure to –15°C compared to placebo. The present study demonstrates for the first time the effects of antihypertensive drugs on BP in hypertensive subjects exposed to cold similar to normal outdoor exposure in winter. Although the magnitude of the cold-induced rise in BP was not affected by the drugs, the drug-induced decrease in the level of BP kept the peak values in the cold closer to the recommended threshold limit values. / Tiivistelmä Tutkimuksen tarkoituksena oli selvittää eri mekanismeilla vaikuttavien verenpainelääkkeiden vaikutusta verenpainevasteisiin ja sydämen lyöntitiheyteen kylmässä sekä verrata erilaisten kylmäaltistusten vaikutusta verenpaineeseen ja sydämen lyöntitiheyteen. Tutkitut lääkkeet edustivat seuraavia verenpainelääkeryhmiä: metoprololi beetasalpaajia, karvediloli yhdistettyjä alfa- ja beetasalpaajia, lisinopriili ACE-estäjiä, eprosartaani angiotensiini II antagonisteja, amlodipiini kalsiumestäjiä ja hydroklooritiatsidi diureetteja. Tärkeimmät mitatut vasteet olivat systolisen ja diastolisen verenpaineen ja sydämen lyöntitiheyden tasot ja muutokset ennen kylmäaltistusta, kylmäaltistuksen aikana ja sen jälkeen. Lisäksi mitattiin lämpötilavasteita ja tuntemuksia. Normo- ja hypertensiiviset koehenkilöt altistettiin joko –15°C:seen 15 minuutin ajaksi (talvivaatetuksessa), 5°C:seen 45 minuutin ajaksi (minimaalisella vaatetuksella) tai tehtiin ns. käden kylmävesitesti (CPT). Testisarjoissa (–15°C) metoprololi, karvediloli, lisinopriili, eprosartaani ja hydroklooritiatsidi tai plasebo annettiin viikon ajan kaksoissokko- ja vaihtovuoromenetelmällä. Yhdessä testisarjassa (5°C ja CPT) koehenkilöt ottivat amlodipiinia 3 päivän ajan tai olivat ilman lääkettä ennen testikertoja vaihtovuoroisessa järjestyksessä. Kaikki kylmäaltistustyypit nostivat merkittävästi sekä systolista että diastolista verenpainetta. Systolisen ja diastolisen verenpaineen nousu oli korkeampi koko kehon kylmäaltistuksissa (5°C tai –15°C) (19–35/20–24 mmHg) kuin ns. kylmävesitestissä (13/16 mmHg). Metoprololi, karvediloli, lisinopriili, eprosartaani ja amlodipiini laskivat verenpaineen tasoja koko kehon kylmäaltistuksessa verrattuna plaseboon. Yksikään verenpainelääkkeistä ei vaikuttanut merkittävästi kylmän aiheuttamaan verenpaineen nousuun verrattuna tutkimuskertaan ilman lääkettä tai plaseboon. Sydämen lyöntitiheys nousi ns. kylmävesitestin aikana, mutta laski koko kehon kylmäaltistuksissa (5°C ja –15°C). Metoprololi ja karvediloli laskivat sydämen lyöntiheyttä kylmäaltistuksessa (–15°C) verrattuna plaseboon. Tämä tutkimus kuvaa ensimmäistä kertaa, kuinka verenpainelääkkeet vaikuttavat verenpainetasoihin ja -vasteisiin kylmäaltistuksessa, joka simuloi tyypillisiä ulko-olosuhteita talvella. Vaikka lääkkeet eivät estäneet kylmän aiheuttamaa verenpaineen nousua, ne laskivat verenpaineen tasoa, jolloin verenpaine pysyi kylmässäkin lähempänä suositusrajoja.