Arterial hypertension it is the leading risk factor for cardiovascular disease. Its prevalence appears to be about 30-45% of the general population. Despite current knowledge the long-term adherence to cardiovascular drugs is still low in hypertension treatment. The Brazilian red propolis has a large content of phenols compounds such as isoflavones, this have been reported to exert beneficial effects in cardiovascular disease, including hypertension. Therefore the objective of this study was to investigate cardiovascular effects from a red propolis gastroretentive system (ESPV, patents register numbers BR 10 2012 013590-6 A2 and WO 2014/186851) in spontaneously hypertensive rats (SHR). The HPLC-UV analysis showed in ESPV chemical composition the presence propolis chemical markers: daidzein, biochanin A, liquiritigenin, pinobanksin, isoliquiritigenin, formononetin and pinocembrina. The cytotoxicity from ESPV was evaluate on macrophage J774 by MTT assay and exhibited IC50 = 72.86 μg/mL. Intravenous injection of ESPV caused a hipotensive dose-dependent effect at 0.1, 0.5, 1, 5 and 10 mg/kg, unchanges heart rate in conscious SHR. The hypotensive effect was not affected by anesthesia. In intact rings of rat mesenteric artery pre-contracted with 10 μM phenylephrine, ESPV induced relaxations (Emax = 100 ± 0.4 %; pD2 = 1.08 ± 0.02 μg/mL) that were affected by endothelium removal, (Emax = 56.7 ± 2 %; pD2 = 1.37 ± 0.04 μg/mL). In an antihypertensive study, ESPV (75 and 150 mg/kg) was orally administered to Juvenile (11-week-old) and young adult (24-week-old) SHRs, and the systolic pressure were measured using the tail-cuff method before and 7, 14, 21 and 28 days after beginning of treatment. Was observed a significant antihypertensive effect from 14th day of treatment only in young adult SHR, with decreased by 56 mmHg compared with baseline systolic blood pressure. Furthermore, the treatment reduced left ventricular hypertrophy in young adult SHR as evident by myocardial morphometry. The vascular function of mesenteric arteries was also investigated at the end of the treatment with ESPV in young adult SHR, the endothelium-independent relaxations to sodium nitroprusside (10-3 to 3.10-4 M) was unchanged compared to control. For other hand, endothelium-dependent relaxations to acetylcholine (10-3 to 3.10-4 M) was markedly improve (Emax = 76.4 ± 3.8% e pD2 = -8.72 ± 3.8 M). We therefore investigated vascular reactivity to acetylcholine (10-3 to 3.10-4 M) also in the presence of the nonspecific NOS inhibitor L-NAME (3.10-3 M), in order to assess NO-dependent relaxation. In these, relaxation response was abolished (Emax = 18.9 ± 1.65% e pD2 = -5.12 ± 0.33 M). Similary, the acetylcholine relaxation in the presence of L-NAME plus a cyclooxygenase antagonist, indomethacin (10-3 M), was too antagonized (Emax = 15.90 ± 1.32 % e pD2 = -5.39 ± 0.24 M), indicating that the response to ESPV treatement involves the enhancement of the nitric oxide via NOS relaxations. These results disclosed that ESPV is effective to lower blood pressure only of young adult SHR, its antihypertensive effect is associated with lowering left ventricular hypertrophy and probably by decrease peripheral vascular resistance, improving endothelial function and increasing the NO-dependent relaxation via NOS. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Estima-se que hipertensão arterial é o principal fator de risco para doença cardiovascular. Sua prevalência parece ser cerca de 30-45% da população mundial. Contudo, apesar do conhecimento atual, a adesão ao tratamento da hipertensão a longo prazo ainda é baixa. A própolis vermelha brasileira apresenta grande teor de compostos fenólicos em sua constituição química, dentre os quais destacam-se as isoflavonas, metabólitos com efeitos benéficos para doenças cardiovasculares, incluindo hipertensão. Desta forma, o objetivo deste estudo foi investigar os efeitos cardiovasculares de um sistema gastrorresistente de própolis vermelha (ESPV, patentes registradas BR 10 2012 013590-6 A2 e WO 2014/186851) em ratos espontaneamente hipertensos (SHR). A análise HPLC-UV demonstrou a presença dos marcadores químicos para propolis na composição química do ESPV: daidzeína, biochanina A, liquiritigenina, pinobanksina, isoliquiritigenina, formononetina e pinocembrina. A avaliação da citotoxicidade de ESPV, em macrófagos J774 através do ensaio de MTT, revelou IC50 = 72,86 μg/mL. A injeção intravenosa de ESPV causou um efeito hipotensor dependente de dose (0,1; 0,5; 1; 5 e 10 mg/kg), sem alterar a freqüência cardíaca em SHR consciente. O efeito hipotensor não foi afetado pela anestesia. Em anéis de artéria mesentérica pré-contraídos com fenilefrina 10 μM, ESPV induziu vasorrelaxamento (Emax = 100 ± 0,4%; pD2 = 1,08 ± 0,02 μg/mL) que foi afetado pela remoção do endotélio (Emax = 56,7 ± 2%; PD2 = 1,37 ± 0,04 μg/mL). Na avaliação do efeito anti-hipertensivo, o ESPV (75 e 150 mg / kg) foi administrado oralmente a SHRs jovens (11 semanas de idade) e adultos jovens (24 semanas de idade), a pressão sistólica foi então avaliada através do método de medida indireta de pressão arterial tail-cuff antes e 7, 14, 21 e 28 dias após o início do tratamento. Desta forma, observou-se um efeito anti-hipertensivo significativo a partir do 14º dia de tratamento apenas em SHR de adultos jovens, com diminuição de 56 mmHg em comparação com a pressão arterial sistólica basal. Além disso, o tratamento reduziu a hipertrofia ventricular esquerda em SHR de adultos jovens como evidenciado pela morfometria miocárdica. Além disso, a função vascular das artérias mesentéricas de SHR tratados com SHR também foi investigada, o relaxamento independente do endotélio foi avaliado através de uma curva concentração-resposta para nitroprussiato de sódio (10-3 – 3.10-4 M), e sob estas condições permaneceram inalteradas em comparação ao controle. Por outro lado, o relaxamento dependentes do endotélio à avaliado através da curva para acetilcolina (10-3 – 3.10-4 M) apresentou melhorara significativa (Emax = 76,4 ± 3,8% e pD2 = -8,72 ± 3,8 M). Por conseguinte, para avaliar o relaxamento dependente de NO, investigou-se a reatividade vascular à acetilcolina (10-3 – 3.10-4 M) na presença do inibidor inespecífico de NOS, L-NAME (3.10-3 M). Nestas condições, a resposta relaxante foi abolida (Emax = 18,9 ± 1,65% e pD2 = -5,12 ± 0,33 M). Resultados similares, foram obtidos ao avaliar o relaxamento da acetilcolina na presença de L-NAME mais um antagonista da ciclo-oxigenase, a indometacina (10-3 M) (Emax = 15,90 ± 1,32% e pD2 = -5,39 ± 0,24 M), indicando que a resposta ao tratamento com ESPV envolve o aumento do relaxamento dependente de óxido nítrico via NOS. Estes resultados revelaram que o ESPV é eficaz para promover redução da pressão arterial apenas de SHR adultos jovens, que o efeito anti-hipertensivo está associado com a redução da hipertrofia ventricular esquerda e provavelmente pela diminuição da resistência vascular periférica, melhorando a função endotelial e aumentando o relaxamento dependente de NO através da NOS.

É plausível que a poluição urbana das grandes metrópoles possa favorecer o desenvolvimento ou mesmo agravar o quadro de hipertensão arterial. A possibilidade de estudar o efeito direto do DE em roedores é extremamente importante e eficaz através do modelo de exposição com o gerador de combustíveis instalado no campus da Faculdade de Medicina da USP. A nossa proposta principal foi avaliar os efeitos hemodinâmicos, aspectos de remodelamento das fibras da matriz extracelular cardíaca e perfil inflamatório pulmonar, visando obter uma conexão entre a exposição ao DE e seus efeitos sistêmicos em 60 ratos hipertensos: SHR (Spontaneously Hypertensive Rats) e 60 normotensos: WKY (Wistar Kyoto). Esses animais foram divididos em 2 grupos: expostos ao ar filtrado e expostos ao diesel e também em 3 tempos de exposição: 15, 30 e 45 dias. Para tanto, foi proposto neste estudo a avaliação dos seguintes parâmetros: Frequência cardíaca, variabilidade da frequência cardíaca, pressão arterial, lavado broncoalveolar, hemograma completo e fatores de coagulação; expressão de marcadores de estresse oxidativo através das análises de citocinas (IL1alfa, IL6, CINC e TNF-alfa) e da enzima superóxido dismutase (SOD) e avaliação qualitativa e quantitativa do tamanho e número de cardiomiócitos e volume de ventrículo esquerdo, através de técnicas estereológicas, e o remodelamento dos elementos fibrilares da matriz extracelular do ventrículo esquerdo dos ratos. Resultados: A exposição DE causou uma diminuição da VFC: SDNN: (p=0,017), RMSSD (p=0,045) nos SHR comparados com WKY todos os tempos de exposição, também foi observado um aumento do tempo de tromboplastina parcial ativada no grupo de 45 dias (p= 0,000), do tempo de protombina nos grupos 30 (p=0,004) e 45 (p=0,000) e uma diminuição da concentração de fibrinogêni no grupo 15 dias (p=0,020). Houve um aumento da concentração de plaquetas nos grupos 30 (p=0,000) e 45 dias (p=0,004) e hipertrofia ventricular esquerda, no grupo 45 dias (p=0,000) para os animais SHR quando comparado aos animais WKY expostos ao DE. Notamos um aumento das fibras colagênicas no grupo 45 dias (p= 0,000) e aumento de volume de cardiomiócitos nos grupos 15 (p= 0,000) 30 (p= 0,000) e 45 dias (p=0,023) em ratos SHR expostos ao DE comparados aos WKY. Também ocorreu um aumento da produção das citocinas IL1beta nos grupos 30 (p=0,002) e 45 dias (p=0,000) e TNF-alfa nos grupos 30 (p=0,012) e 45 dias (p=0,003) e CINC no grupo 45 dias (p= 0,021) em ratos SHR expostos ao DE. Comparando as linhagens, os ratos SHR expostos ao DE apresentaram maiores valores de IL1? no grupo 45 dias (p=0,043). Os valores de SOD foram menores em ratos SHR no grupo 30 dias (p= 0,016) de exposição ao DE. Nos ratos SHR, expostos ao DE, nos grupos 30 (p= 0,008) e 45 dias (p= 0,002), notou-se um aumento de macrófagos no lavado broncoalveolar. Conclusões: De acordo com esses achados, notamos que a exposição ao diesel promove inflamação pulmonar e sistêmica, desbalanço do sistema nervoso autônomo e remodelamento do miocárdio em animais hipertensos. Estes fatores poderão promover ou agravar os quadros de hipertensão arterial sistêmica em indivíduos suscetíveis e expostos a poluição urbana / The expousure to DEP (Diesel Exhaust Particles) it is related to oxidative stress, it is possible that air pollution of the cities may aggravate hypertension. The possibility of studying the direct effects of DEP in rats it is important and effective through intoxication model with the fuel generator installed in Medicine University of USP. The fuel generator system possible to evaluate the toxicological risks to the use of diesel. The study allowed hemodynamics effects, remodeling of left ventricle, pulmonary inflammation, having the connection between exposure to DEP and your systemic effects. It was evaluated: heart rate, heart rate variability, blood pressure, bronchoalveolar lavage, complete blood count and coagulation factors, citokines evaluation (IL1beta, 1L6, CINC and TNF-alpha) and SOD, vascular endothelium peribronchial vessels in bronchoalveolar lavage through immunoassay and qualitative and quantitative remodeling of extracellular matrix elements in left ventricle of 60 rats hypertensive: SHR (Spontaneosly Hypertensive Rtas) and 60 normotensive WKY (Wistar Kyoto). This animals were divided in 2 groups: exposed to filtred air and exposed to diesel and to 3 times exposures groups: 15, 30 and 45 days. Results: The DE exposure caused decreased in HRV: SDNN: (p=0,017), RMSSD (p=0,045) in SHR in all times of exposure, increased in the values of coagulation factors in SHR exposed to DE after 30 (p=0,001) and 45 days (p=0,000), an aggregation of platelets after 30 (p=0,000) and 45 days (p=0,004), and left ventricular hypertrophy after 45 days (p=0,000) in SHR exposed to DE. We noticed an increase in colagenous fibers after 45 days (p= 0,000) in SHR rats exposed to DE and increased volume of cardiomyocytes after 15 (p= 0,000), 30 (p= 0,000) and 45 days (p=0,023). A increased in citokines production IL1beta after 30 (p=0,002) and 45 days (p=0,000) e TNF-alpha after 30 (p=0,012) and 45 days (p=0,003) and CINC after 45 days (p= 0,021) in SHR exposed to DE. Comparing the lineages, the SHR exposed to DE presented increased in values of IL1beta after 45 days (p=0,043). The SOD values increased in SHR after 30 days (p= 0,016) of exposure to DE. In SHR exposed to DE presented increased after de 30 (p= 0,008) and 45 days (p= 0,002), in values of macrophages. Conclutions: According to these findings, we noticed that exposure to diesel can promote pulmonary and systemic inflammation, imbalance the autonomic nervous system and remodeling the myocardium. These factors may promote or worsen hypertension in susceptible individuals exposed to urban pollution

Ground source heat pumps (GSHPs) offer an efficient method for cooling and heating buildings, reducing energy usage and operating cost. In hot, arid regions such as Texas and the southwest United States, building load imbalance towards cooling causes design and performance challenges to GSHP systems in residential and commercial building applications. An integrated building load and GSHP model is developed in this thesis to test approaches to reduce GSHP cost, to properly size ground heat exchanger (GHEX) installations and to offer methods to improve GSHP performance in commercial buildings. The integrated model is comprised of a three-story office building, heat pumps, air handling system and a GHEX. These component models were integrated in the Matlab® Simulink® modeling environment, which allows for easy model modification and expansion. The building-load model was developed in HAMBASE, which simulates the thermal and hygric response of each zone in the building to external weather and internal loads. The building-load model was validated using the ASHRAE 140-2007 Standard Method of Test and with results from EnergyPlus. The heat pump model was developed as a performance map, based on data commonly provided by heat pump manufacturers. This approach allows for easy expansion of the number and type of heat pump models supported. The GHEX model was developed at Oklahoma State University and is based on Eskilson’s g-function model of vertical borehole operation. The GHEX model accurately represents the interaction between boreholes and the ground temperature response over short and long time-intervals. The GHEX model uses GLHEPRO files for parameter inputs. Long time-interval simulations of the integrated model are provided to assess the sensitivity of the GSHP system to various model parameters. These studies show that: small changes in the total GHEX length reduce system cost with minimal impact on performance; increased borehole spacing improves system performance with no additional cost; supplemental heat rejection reduces installation costs and improves system performance; industry-recommended design cutoff temperatures properly size the GHEX system; and, while cooling is the greatest contributor to operating cost in the southwest and southcentral United States, heating is the limiting design case for GHEX sizing. / text

Resumo: A hipertensao arterial representa um fator de risco sistemico e condicao desfavoravel para tratamentos dentarios, especialmente aqueles que necessitam de reparacao ossea. O objetivo deste estudo foi avaliar o reparo alveolar em ratos espontaneamente hipertensos (SHR) e o efeito do atenolol sobre este processo. Wistar e SHR tratados ou nao com 100mg/kg/dia (atenolol), foram submetidos a extracao do dente incisivo superior direito e sacrificados aos 7, 14, 21, 28 e 42 dias apos a cirurgia. As hemi-maxilas foram removidas e as imagens radiograficas foram realizadas. A analise radiografica foi obtida por meio do sistema digital Digora. Analises histologicas, histomorfometricas e reacoes imunoistoquimicas foram feitas em cortes histologicos de 5ƒÊm de espessura, os quais foram corados com hematoxilina-eosina ou submetidos a imunomarcacao para RANK, RANKL, OPG e proteinas MMP-9. A analise histologica foi realizada por microscopia optica e a analise histomorfometrica pelo software RGB / Leica Qwin Color. Os resultados densitometricos e histomorfometricos foram analisados pela Anova two-way. Na analise imunoistoquimica, utilizando um microscopio optico, foram atribuidos scores as imagens. Os resultados foram analisados pelos testes estatisticos Kruskal-Wallis e Mann Whitney. As diferencas entre os resultados foram consideradas significativas quando p<0,05. Reducao da densidade mineral ossea (DMO), menor porcentagem de osso e menor espessura do trabeculado osseo foram observadas nos periodos finais do reparo alveolar em SHR. Aumento da imunomarcacao para RANKL, RANK e MMP-9 foi observado em 28 dias apos a cirurgia no alveolo em SHR. Consistente efeito do atenolol foi observado no reparo alveolar de ratos hipertensos. O atenolol aumentou a DMO observada na maioria dos periodos analisados e aumentou a espessura do trabeculado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Hypertension represents a systemic risk factor and unfavorable condition for dental treatments, especially treatments that require bone healing. The purpose of this study was to evaluate the alveolar wound healing in spontaneously hypertensive rats (SHR) and the atenolol effect on this process. Normotensive Wistar rats and SHR, untreated or treated with atenolol (100mg/kg/day), were submitted to the extraction of the upper right incisive tooth and sacrificed at 7, 14, 21, 28 and 42 days after surgery. The hemi-jaws were extracted and the radiographic images were obtained. Radiographic analysis was performed by using the digital system Digora. Histological, histomorphometric and immunohistochemical reactions were done in histological sections, 5 μm thick, stained with hematoxylin and eosin or subjected to immunolabeling to RANK, RANKL, OPG and MMP-9 proteins. Histological analysis was performed by light microscopy and histomorphometric analysis by Leica Qwin Color/RGB software. The densitometric and histomorphometric results were also analyzed by two-way ANOVA. In immunohistochemical analysis, using an optical microscopy, scores were assigned to the images. Results were analyzed by Kruskal-Wallis and Mann Whitney statistical tests. Differences between results were considered significant when p <0.05. Reduced bone mineral density (BMD), lower bone percentage and less thickness of trabecular bone was observed in the final periods of alveolar bone healing in SHR. Increased RANKL, RANK and MMP-9 immunolabeling were observed at 28 days after surgery in SHR alveolus. Consistent atenolol effect was observed on alveolar bone healing of hypertensive rats. Atenolol increased the BMD observed in most of the periods analyzed and increased trabecular bone thickness at 28 and 42 days in SHR alveolus. Increased OPG immunolabeling... (Complete abstract click electronic access below) / Orientador: Cristina Antoniali Silva / Coorientador: Roberta Okamoto / Banca: Raquel Fernanda Gerlach / Banca: Sandra Helena Penha de Oliveira / Mestre

Ground source heat pumps (GSHP) have the ability to significantly reduce the energy required to heat and cool buildings. Historically, deployment of GSHP's in the cooling-dominated Texas and Southwest region has been significantly less than in other regions of the United States. The long term technical and economic viability of GSHPs in arid regions such as Texas has been questioned due to failures of ground loop heat pump systems by early adopters. A proposed solution is to include a supplemental heat rejection (SHR) device to help offset the unbalanced ground loads. An integrated building load-ground source heat pump model is developed in this thesis and is designed to be a test bed for potential SHR devices. The model consists of discrete component models that can be mixed and matched to represent various types of buildings and ground source heat pumps. One of the unique features of the integrated model is the use of the Simulink/Matlab environment. This environment allows the user to develop component models that take advantage of the built-in functionality of Matlab and Simulink. Another unique feature is the full coupling of the building load, heat pump, and ground loop at every time step. The building load, heat pump, and ground loop models were chosen to allow for short time step simulations, which allows for a range of dynamic response times to be modeled and for different heat pump/SHR control methods to be explored. The integrated model can be used on any computer that has the Matlab and Simulink software. The building load model used, called HAMBASE, can model both residential and commercial buildings. HAMBASE was validated using the ASHRAE 140-2007 standard. The heat pump model uses readily available data provided by GSHP manufacturers to accurately model operation across a wide range of input conditions. The vertical borehole ground loop model, developed at Oklahoma State University, is based on Eskillson's g-function model, but included a one-dimensional numerical model to calculate the short term thermal response of the borehole and ground. The ground loop model utilizes GLHEPRO, a ground loop sizing and simulation tool, to create the required parameter files. Using the integrated building load-ground source heat pump model, a model of a single family house with a ground source heat pump was developed. The house model was validated by the results from eQuest and GELHPRO. A series of sensitivity studies were completed to determine dominant factors affecting the use of GSHPs in Texas and the Southwest regions of the United States. The results show that the life of a vertical borehole can be significantly extended/cut short if the ground parameters are properly/not properly designed prior to ground loop sizing. / text

Contribuant à la pathophysiologie des maladies vasculaires comme dans le cas de l’hypertension, le remodelage vasculaire est associé à une altération de la croissance des cellules musculaires lisses vasculaires (CMLV) (prolifération, taille, etc.). Or la prolifération des CMLV est augmentée par les peptides vasoactifs tels que l’angiotensine II (AngII) et l’endothéline-1 (ET-1). Ces peptides étant surexprimés lors de l’hypertension, cette étude fut entreprise pour déterminer leur contribution endogène ainsi que celles du facteur de croissance épidermique (EGF), du facteur de croissance insulinique (IGF-1) et du facteur de croissance dérivé des plaquettes (PDGF) à la prolifération accrue des CMLV et aux mécanismes sous-jacents. Des CMLV A-10 et des CMLV de rats WKY et SHR âgés de 12 semaines ont été utilisées pour cette étude. La prolifération cellulaire fut déterminée par incorporation de [3H]thymidine. La phosphorylation de ERK 1/2 et du récepteur de EGF fut déterminée par immunobuvardage. Les CMLV de SHR, comparées à celles de WKY, ont montré une prolifération accrue qui fut atténuée par le losartan, un antagoniste du récepteur AT1 de l’AngII et par le BQ-123 et le BQ-788, antagonistes des récepteurs ETA et ETB de l’ET-1. La prolifération accrue des CMLV de SHR fut ramenée à celle des WKY par les inhibiteurs des récepteurs au PDGF (AG-1295), au IGF-1 (AG-1024) et au EGF (AG-1478). La phosphorylation du récepteur au EGF, accrue dans les CMLV de rats SHR comparée à celle des WKY, fut atténuée par le losartan, le BQ-123, le BQ-788 et l’AG-1478, mais ne fut pas atténuée par l’AG-1295 et l’AG-1024. De plus, la phosphorylation accrue de ERK 1/2 dans les CMLV de rats SHR fut atténuée par le losartan, le BQ-123, le BQ-788 et les inhibiteurs des récepteurs aux facteurs de croissance. Parallèlement, le rôle de la transactivation de EGF-R dans la prolifération accrue induite par AngII et ET-1 fut aussi examiné dans les CMLV A-10. L’augmentation, induite par AngII et ET-1, de la prolifération et de la phosphorylation de ERK 1/2 dans les CMLV A-10 fut ramenée au niveau contrôle par AG-1478. Ces données suggèrent que les peptides vasoactifs endogènes induisent la prolifération accrue des CMLV par la signalisation des MAP kinases résultant de la transactivation de EGF-R. / Vascular remodelling that contributes to the pathophysiology of vascular diseases, including hypertension, is associated with alteration in vascular smooth muscle cell (VSMC) growth, hypertrophy, etc. We have recently shown that vasoactive peptides such as angiotensin II (AngII) and endothelin-1 (ET-1) increased the proliferation of VSMC. Since the levels of AngII, ET-1 and growth factors are increased in hypertension, the present studies were undertaken to examine if these endogenous vasoactive peptides and growth factors contribute to the enhanced proliferation of VSMC in spontaneously hypertensive rats (SHR) and to further investigate the underlying mechanisms responsible for enhanced proliferation. A10 VSMC and aortic VSMC from 12 week old SHR and age-matched WKY rats were used for these studies. Cell proliferation was determined by [3H]thymidine incorporation and ERK ½ and growth factor receptor phosphorylation was determined by Western blotting. VSMC from SHR exhibited enhanced cell proliferation as compared to WKY as determined by enhanced [3H]thymidine incorporation which was attenuated by AngII AT1 receptor antagonist losartan, as well as by endothelin receptor ETA and ETB antagonists BQ-123 and BQ-788, respectively. The inhibitors of platelet derived growth factor receptor (PDGF-R); AG-1295, epidermal growth factor receptor (EGF-R); AG-1478, and insulin-like growth factor receptor (IGF-R); AG-1024 also attenuated the enhanced proliferation of VSMC from SHR to WKY control levels. In addition, VSMC from SHR exhibited enhanced phosphorylation of EGF-R as compared to WKY, which was attenuated by losartan, BQ-123, BQ-788 and AG-1478, and not by AG-1295 and AG-1024. Furthermore, the enhanced phosphorylation of ERK ½ in VSMC from SHR was also attenuated by losartan, BQ-123 and BQ-788 as well as by growth factor receptor inhibitors, AG-1478, AG-1024 and AG-1295. The implication of growth factor receptor transactivation in AngII and ET-1 induced enhanced cell proliferation was also examined in A10 VSMC. Ang II or ET-1 induced enhanced proliferation of A-10 VSMC and enhanced ERK ½ phosphorylation was also restored to control levels by EGF-R inhibitor. These data suggest that vasoactive peptide-induced growth factor receptor transactivation through MAP kinase signaling may contribute to the enhanced proliferation of VSMC from SHR.

Made available in DSpace on 2014-06-11T19:23:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-07-20Bitstream added on 2014-06-13T20:50:30Z : No. of bitstreams: 1 potje_sr_me_araca.pdf: 486426 bytes, checksum: fbbc778d219e6341b4ac4c430b070e73 (MD5) / O efeito hipotensor do TERPY é aumentado em SHR em comparação com ratos normotensos Wistar (WST), mas o seu relaxamento em anéis de aorta sem endotélio não difere entre os grupos. Trabalhamos com a hipótese de que o desacoplamento da óxido nítrico sintase (NOS) ou espécies reativas de oxigênio (EROs) podem prejudicar a biodisponibilidade de óxido nítrico (NO) liberado pelo TERPY e NPS (nitroprussiato de sódio) em seus efeitos hipotensores e vasodilatadores em SHR. Avaliamos o efeito do L-NAME (inibidor da NOS), da APOCININA (bloqueadora da NOX) e do TEMPOL (mimético da superóxido dismutase) na resposta hipotensora e na vasodilatação induzida pelos doadores de NO, TERPY e NPS, em aortas de WST e SHR. L-NAME aumentou o efeito hipotensor do TERPY em WST, mas não em SHR. Este efeito não foi alterado pelo TEMPOL, mas foi aumentado pela APOCININA em ambos os grupos. Essas drogas não alteraram o efeito hipotensor do NPS. A remoção do endotélio ou incubação com L-NAME diminuiu a potência do TERPY na aorta de SHR e aumentou na aorta de WST. TEMPOL e APOCININA aumentaram a potência do TERPY em aortas de WST e de SHR. Estes efeitos são independentes do endotélio em SHR e sensíveis ao endotélio em WST. A presença do endotélio e a incubação com TEMPOL ou APOCININA aumentou a potência do NPS em aortas de WST e SHR. Em conclusão, o efeito hipotensor do TERPY é prejudicado pela NOS em WST e pela NOX em WST e SHR. Por outro lado, o efeito hipotensor do NPS é semelhante em WST e SHR, que é independente da NOS e de EROs. Em aortas, EROs derivadas do endotélio prejudicam o relaxamento do TERPY em anéis de aorta de WST e SHR, e EROs liberadas a partir de células do músculo liso vascular (CMLV) também participam dessa resposta apenas em aortas de SHR / The hypotension of TERPY is increased in SHR compared to Wistar (WST) rats, but its relaxation in denuded aortic rings is not different. We hypothesized that NO-synthase uncoupling or reactive oxygen species (ROS) could impair the NO bioavailability released from TERPY and SNP in their hypotensive and vasorelaxant effects in SHR. We evaluated the effect of the inhibitors L-NAME (NO-synthase) and APOCYNIN (NOX), and TEMPOL (superoxide dismutase mimetic) in the hypotensive effect and aorta vasodilatation induced by NO-donors in WST and SHR. L-NAME increased TERPY's hypotensive effect in WST, but not in SHR. This effect was not altered by TEMPOL, but it was increased by APOCYNIN in both groups. These drugs did not alter the SNP's hypotensive effect. Endothelium removal, or L-NAME, decreased the potency of TERPY in SHR aorta and increased it in WST aorta. TEMPOL and APOCYNIN increased the potency of TERPY in WST and SHR aortas. These effects are endothelium independent in SHR, and endothelium dependent in WST. Endothelium, TEMPOL and APOCYNIN increased the potency of SNP in aortas of WST and SHR. In conclusion, TERPY's hypotensive effect is impaired by NOS in WST and by NOX activity in WST and SHR. Otherwise, the hypotensive effect of SNP is similar in WST and SHR, which is independent of NOS and ROS. In aortas, ROS derived from endothelium impairs the relaxation of TERPY in aortic rings of WST and SHR, but ROS from vascular smooth muscle also participates in this response in SHR aorta

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Made available in DSpace on 2016-03-15T14:19:06Z (GMT). No. of bitstreams: 2 bruno_sabino_ioc_dout_2008.pdf: 177162 bytes, checksum: da8f12caaae52be69499e9626f0f4a5b (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2016-01-13 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Introdução: A elevação crônica da resistência vascular sistêmica pode ser considerada como a principal alteração hemodinâmica na hipertensão arterial primária estabelecida. Investigamos os efeitos do tratamento crônico com os anti-hipertensivos atenolol (ATE), enalapril (ENA), nifedipina (NIF) e losartan (LOS) sobre a densidade capilar funcional média (DCFM) cutânea e muscular esquelética (grácil) e sobre a densidade capilar estrutural muscular esquelética e do ventrículo esquerdo de SHR. Métodos: Ratos SHR machos com 12-14 semanas receberam tratamento oral por gavagem com ATE (50 mg/kg/dia), NIF (20mg/kg/dia), LOS (10 mg/kg/dia) ou veículo (grupo controle) durante quatro semanas. Após o término do tratamento avaliou-se a DCFM através de microscopia intraviral por epi-iluminação com fluorescência. A seguir, foi avaliada a densidade capilar estrutural através de histoquímica em parafina. Resultados: o tratamento reduziu de forma similar a pressão arterial sistólica de SHR tratados com ATE, ENA, NIF ou LOS. A DCFM encontrava-se diminuída em SHR no músculo esquelético (WKY 395±17 e SHR 258±13 capilares/mm2, p<0,01) ou pele (WKY 391±18 e SHR 210±15 capilares/mm2, p<0,01). LOS e NIF reverteram completamente este quadro em ambos os tecidos (434±26e 422±18 capilares/mm2 no músculo esquelético e 397±31 e 391±24 capilares/mm2 na pele, p<0,01, respectivamente), enquanto o ENA aumentou significativamente a DCFM apenas na pele de SHR (283±17, p<0,05 capilares/mm2). O ATE não induziu nenhuma alteração na DCFM de SHR. Foi observada uma relação linear entre a densidade capilar funcional no músculo esquelético e na pele (r=0.654, p<0.0001) Na análise estrutural, foi observada uma relação capilar/fibra significativamente menor no músculo esquelético de SHR (WKY 1,74±0,08 e SHR 1,40±0,06, p<0,01), que foi revertida pelos tratamentos com ENA, NIF e LOS (1,65±0,04; 1,78±0,1 e 1,8±0,07, p<0,01, respectivamente). A razão entre a densidade de volume de capilares e a densidade de volume de fibras (Vv[cap] / Vv[fib]) do ventrículo esquerdo de SHR também foi significativamente reduzida (WKY 0,55±0,09 e SHR 0,42±0,09, p<0,01). Os tratamentos com LOS ou ENA reverteram completamente a rarefação estrutural cardíaca de SHR (0,59±0,03 e 0,59±0,03, p<0,01, respectivamente), enquanto os tratamentos com ATE e NIF não apresentaram nenhum efeito. Discussão: Os resultados obtidos indicam que os efeitos microcirculatórios de diferentes drogas anti-hipertensivas diferem entre as classes farmacológicas e vão além da redução da pressão arterial. Este conceito pode ser útil para guiar o tratamento anti-hipertensivo na tentativa de reduzir ou até mesmo reverter as lesões de órgãos-alvo / ntroduction: It is well known that the major part of the increased vascular resistance in hypertensio n is determined at the microvascular level, resulting ma inly from functional (changes in vascular reactivit y) and/or structural (increased arteriolar wall thickness) ab normalities. We investigated the effects of chronic oral antihypertensive treatment on functional and struct ural capillary rarefaction in spontaneously hyperte nsive rats (SHR). Wistar Kyoto rats (WKY) were used as a normo tensive control group. Methods: Male SHR (12 14 weeks) received oral treatment with the ß blocker a tenolol (ATE) (50 mg/kg/day), angiotensin convertin g enzyme (ACE) inhibitor enalapril ENA (10 mg/kg/day) , the calcium channel blocker nifedipine NIF (20mg/kg/day), the angiotensin II type I receptor ( AT1) receptor antagonist losartan LOS (10mg/kg/day) , or vehicle (control group) during four weeks. At the e nd of the treatment, the functional capillary densi ty (FCD) was evaluated by intravital videomicroscopy with fluore scence. Then, we evaluated the structural capillary density (SCD) by immunohistochemistry embedded in paraffin. Results: In untreated rats, the FCD was lower in S HR skeletal muscle (WKY 395±17 and SHR 258±13 capillar ies/mm2, P<0.01) and ear skin (WKY 391±18 and SHR 210±15 capillaries/mm2, P<0.01). A linear relations hip was seen between skeletal muscle and skin capil lary densities (r=0.654, P<0.0001). Histologic analysis showed that SHR had a lower capillary to fiber rati o in the skeletal muscle (WKY 1.74±0.08 and SHR 1.40±0.06, P <0.01). Capillary volume density to fiber volume density ratio in the left ventricle of SHR was also reduced (WKY 0.55±0.09 and SHR 0.42±0.09, P<0.01). The pharmacological treatment with ENA, LOS, ATE, or NI F, resulted in similar reductions in systolic blood pressure (19.8%, 19.1%, 17.4%, and 18.2%, respectiv ely, P<0.05). ATE did not induce any change in func tional capillary density of SHR. LOS and NIFE completely r eversed functional capillary rarefaction in both mu scle and cutaneous tissues (434±26 and 422±18 capillaries/mm 2 in skeletal muscle and 397±31 and 391±24 capillaries/mm 2 in skin, p<0,01, respectively), whereas ENA signif icantly increased functional capillary density only in the skin. The skeletal muscle capillary to fiber ratio was normalized by ENA, LOS, and NIF (1, 65±0,04; 1,78±0,1 and 1,8±0,07, p<0,01, respectively). Treat ments with ENA or LOS normalized the cardiac struct ural capillary rarefaction of SHRs (0,59±0,03 and 0,59±0 ,03, p<0,01, respectively), whereas ATE and NIF had no effect. Discussion: Our results suggest that differ ent pharmacologic classes of antihypertensive drugs with similar effect on blood pressure differ in terms of their e ffect on the microcirculation. This concept could b e useful to guide the pharmacological treatment of hypertension , in order to reduce or even revert the target orga n damage

Made available in DSpace on 2014-06-11T19:25:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-07-31Bitstream added on 2014-06-13T19:53:31Z : No. of bitstreams: 1 000741594.pdf: 1238321 bytes, checksum: 928f3598dad58d02baa22076c51e969a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / As enzimas NAD(P)H oxidases ou família NOX tem sido considerada a principal fonte de espécies reativas de oxigênio (ERO) em vários tipos celulares. O aumento da biodisponibilidade de ERO e do sinal redox (estresse oxidativo) têm sido associados ao início e ou progressão de doenças crônicas como a hipertensão. Inibidores da NAD(P)H oxidase, como a apocinina, foram desenvolvidos e seus efeitos anti-hipertensivos têm sido estudados. O objetivo deste estudo foi verificar se o tratamento crônico com apocinina previne o desenvolvimento da hipertensão, da disfunção endotelial e da hipertrofia ventricular esquerda em Ratos Espontaneamente Hipertensos (SHR) e avaliar os possíveis mecanismos envolvidos nestes efeitos. Para isto, ratos normotensos Wistar e SHR foram tratados com apocinina (30 mg/kg/dia, diluída na água de beber) da quarta até a décima semana de vida. Foram realizados experimentos in vivo para avaliação de valores basais de pressão arterial (média - PAM, sistólica - PS e diastólica - PD), freqüência cardíaca (FC) e as respostas às drogas hipotensoras, acetilcolina (ACh) e nitroprussiato de sódio (NPS) e pressoras, fenilefrina (Phe) e angiotensina II (ANGII). Experimentos in vitro foram realizados para determinar se o tratamento com apocinina promove alterações na concentração citosólica de cálcio intracelular ([Ca2+]), de óxido nítrico ([NO]) e de espécies reativas de oxigênio ([ERO]) nas células endoteliais (citometria de fluxo), estimuladas ou não com acetilcolina; na expressão proteica (Western Blotting) de enzima óxido nítrico sintase endotelial... / The enzymes NAD(P)H oxidases or family NOX has been considered the main source of reactive oxygen species (ROS) in various cell types. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. NAD(P)H oxidase inhibitors, such as apocynin were developed and their antihypertensive effects have been studied. The aim of this study was to determine whether chronic treatment with apocynin prevents the development of hypertension, endothelial dysfunction and left ventricular hypertrophy in spontaneously hypertensive rats (SHR) and to evaluate the mechanisms involved in these effects. Normotensive Wistar rats and SHR were treated with apocynin (30 mg/kg/day, diluted in the drinking water) from the fourth to the tenth week of life. The studies in vivo were performed to assess baseline blood pressure (mean arterial pressure - MAP, systolic - SBP, and diastolic blood pressure - DBP), heart rate (HR) before and after the administration of acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (Phe) and angiotensin II (ANG II). We performed experiments in vitro to determine whether the treatment with apocynin causes changes in: cytosolic concentration of intracellular calcium ([Ca2+]), nitric oxide ([NO]), and reactive oxygen species ([ROS]) in endothelial cells (flow cytometry) stimulated or not with acetylcholine; protein expression (Western blotting) of enzyme endothelial nitric oxide synthase (eNOS) and of soluble guanylate cyclase... / FAPESP: 11/04619-0 / FAPESP: 11/20998-0