Farah MCK. Disfunção ventricular no pós-operatório da intervenção cirúrgica para correção dos defeitos congênitos da Tetralogia de Fallot. Estudo de correlação clínica e anatomopatológica [tese]. São Paulo: Faculdade de Medicina, Universidade de São Paulo; 2008. 136p. O estudo investigou de modo prospectivo o remodelamento ventricular histopatológico em crianças submetidas à correção cirúrgica de Tetralogia de Fallot (TF) com o objetivo de detectar possíveis fatores associados aos indicadores ecocardiográficos de disfunção ventricular sistólica e diastólica no período pós-operatório. Pacientes e métodos: foram incluídos 23 pacientes consecutivos portadores de TF (14 masculinos), com idade entre 12 e 186 meses (média=39,6 meses, mediana = 23 meses). A análise do Doppler Tecidual (índice de aceleração isovolumétrica - AVI, velocidade miocárdica sistólica - S\', velocidade miocárdica diastólica precoce - E\') foi realizada em três momentos: antes da cirurgia, nos primeiros três dias de PO e entre 30 a 90 dias após a cirurgia. Durante a cirurgia, além das bandas musculares infundibulares, foram obtidas biópsias subendocárdicas na via de entrada do VD e do VE. Foram avaliados quanto ao grau de hipertrofia miocárdica, colágeno intersticial (picorsirius) e capilaridade (imunohistoquímica-fator VIII). Níveis séricos de troponina T foram mensurados antes e após a cirurgia. Eletrocardiogramas realizados antes e após a cirurgia, características clínicas e uso prévio de propranolol foram avaliados. Este estudo foi aprovado pela comissão de ética da CPPESQUSP. Resultados: Os cardiomiócitos do VD mostraram acentuada hipertrofia. O colágeno intersticial esteve aumentado em ambos os ventrículos. A área ocupada por capilares não diferiu entre as diversas regiões estudadas. Houve diminuição significativa do AVI do VD no terceiro ecocardiograma (p=0,006) o que se correlacionou de modo negativo e significativo com o diâmetro dos cardiomiócitos da via de entrada do VD (r=-0,59; p=0,006). As velocidades de E\' do VD, diminuíram significativamente nos dois períodos pós-operatórios (p<0,001) e tiveram correlação negativa significativa com a porcentagem de colágeno intersticial (r= -0,525; p=0,004). Os níveis séricos de Troponina T aumentaram significativamente em todos os pacientes no período pós-operatório- 27,7 ±18,6 ng/ml e 15,9+11,3 ng/ml respectivamente no segundo e terceiro PO e se correlacionaram de modo positivo e significativo com o tempo de circulação extra corpórea e com o tempo de anoxia (p=0,019 e 0,018, respectivamente) e maior tempo de uso de droga vasoativa no pós-operatório (r=0,552, p=0,006). A duração do QRS aumentou significativamente no PO. Os pacientes que apresentaram aumento do QRS maior que 40ms, também apresentaram maior porcentagem de colágeno intersticial na via de entrada do VD. Conclusão: o remodelamento miocárdico presente no período pré-operatório, a julgar pela avaliação histopatológica morfométrica da hipertrofia celular e colágeno intersticial, influenciou respectivamente a função sistólica e diastólica do ventrículo direito no período pós-operatório da correção cirurgia da Tetralogia de Fallot. / It was investigate prospectively the histopathological myocardial remodeling in children submitted to surgical repair of Fallot\'s tetralogy, in order to detect possible factors associated to postoperative (PO) echocardiographic findings of systolic or diastolic ventricular dysfunction. Patients and Methods: 23 consecutive Fallot patients (14 males), aged 12 to 186 months (mean=39.6, median=23 months) were enrolled in the study. Tissue Doppler echocardiographic analysis (isovolumic acceleration-IVA, systolic myocardial velocity-S\' and early diastolic myocardial velocity-E\') was performed in three moments for both ventricles: before surgery, within the first three postoperative days and later, between the 30th and 90th PO days. During surgery, besides the anomalous infundibular bands resected, subendocardial biopsy samples from the right ventricular (RV) inflow tract and of the left ventricle (LV), through the ventricular septal defect, were obtained for histopathological morphometric evaluation: degree of cell hypertrophy, interstitial collagen (Sirius-red) and capillarity (immunohistochemistry against Factor-VIII). Troponin-T levels were measured before and after surgery. The electrocardiogram performed before and after surgery, some clinical features and previous use propranolol were considered. This study was approved by the Ethical Committee of our Institution. Results: the right ventricular cardyomyocytes showed a significant hypertrophy. The interstitial collagen was increase in both right and left ventricle. The capillary area fraction did not differ among the biopsy samples analyzed. IVA of the RV decreased significantly at the third echocardiographic evaluation (p=0.006) and correlated negatively with the diameter of the RV cardyomyocytes (r= -0.59; p=0.006). E\' measured at the RV decreased significantly in both PO periods (p<0.001) and showed a significant negative correlation with the percentage of interstitial myocardial collagen (r=-0.525; p=0,044). Troponin-T levels increased postoperatively in all patients (27.7 ±18,6ng/ml and 15.9+11.3ng/ml - second and third PO days) and correlated positively with the cardiopulmonary bypass and cross clamping times (p=0.019 and 0.018 respectively). The QRS interval increased significantly in the PO period. The patients in whom the PO electrocardiogram showed an increase of the QRS greater than 40ms, showed a greater interstitial collagen area fraction in the right ventricle inflow tract. Conclusions: Myocardial remodeling present preoperatively, as judged by the morphometric histopathological evaluation of cell hypertrophy and interstitial collagen, influenced respectively the medium term PO systolic and diastolic right ventricular function of repaired Fallot patients.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

This thesis examines the overarching theme of inhaled corticosteroid (ICS) dose response effects on a variety of asthma outcome measures; with further importance placed on the application of these findings to personalising ICS dosing for the individual asthmatic. The introduction provides a detailed summary of the current recommendations for the treatment of adult asthma, with particular reference to the mechanism of action and clinical utility of ICS for the treatment of asthma. Current methods of assessing ICS dose response are presented, as well as the common influences that affect these responses. Novel therapeutic theories and the identification of specific asthmatic phenotypes are also introduced, in order to demonstrate the shift towards personalising treatment for asthma. The first two studies examine the dose response of ICS on two specific factors that influence asthma. The third study presents an examination of pharmacological manipulation of the ICS dose response using an additional agent. The following two studies address: how asthma outcomes relate to each other in patients receiving ICS; in addition to an overall assessment of the ICS dose response across a broad range of both ICS moieties and outcome measures. The final study examines for any detrimental effect of an ICS dose ramp on bone metabolism, an important potential long-term adverse effect of higher ICS dosing. The discussion draws together all the results obtained in relation to ICS dose response in asthma, and how these apply to current clinical practice for the individual patient. Furthermore, hypotheses are generated for areas of future study based on the findings from this work.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia. / Made available in DSpace on 2012-10-22T15:02:55Z (GMT). No. of bitstreams: 1 225418.pdf: 2520051 bytes, checksum: b59986e81eda2d965b91443a5dedb96d (MD5) / Estudos têm demonstrado que o odor do predador é um potente estímulo ansiogênico, fornecendo elementos para a avaliação do comportamento defensivo natural em roedores. Durante situações de estresse ou perigo potencial, a liberação de adrenalina ocasiona ativação de receptores beta-adrenérgicos nas vias ascendentes do vago para estruturas do SNC envolvidas na expressão e consolidação do medo e de suas respostas defensivas. O objetivo principal do presente estudo foi avaliar a participação do sistema beta-adrenérgico no comportamento defensivo de ratos expostos ao modelo do odor de gato. Para este propósito, realizamos inicialmente uma validação biológica e farmacológica do modelo dentro das condições experimentais de nosso laboratório. Em seguida, avaliamos o papel da neurotransmissão beta-adrenérgica central e periférica na resposta defensiva de ratos submetidos a este modelo. Nesta etapa, utilizamos em nossos estudos antagonistas beta-adrenérgicos como o propranolol, com ações farmacológicas centrais e periféricas, e o nadolol, com ações restritas à periferia. Por fim, avaliamos o envolvimento da neurotransmissão noradrenérgica do núcleo PMd - uma estrutura hipotalâmica amplamente relacionada ao comportamento defensivo inato - sobre a resposta defensiva de ratos expostos ao odor de gato, através da microinjeção de atenolol, um bloqueador beta1 seletivo, diretamente nesta estrutura. Nossos resultados demonstraram que a injeção sistêmica de propranolol, bem como as microinjeções de atenolol no PMd, foram eficazes na redução da resposta defensiva. Estes achados sugerem uma participação do sistema beta-adrenérgico central, além de reforçar o papel chave do PMd no comportamento de defesa inato frente ao odor de gato. Substantial evidences have been showing that predator odor is a powerful anxiogenic stimulus, providing insights into natural defensive behavior evaluation in rodents. During situations of stress or potential danger, epinephrine release actives beta-adrenoreceptors on the ascending vagus, projecting to central nervous system structures, which are believed to be important in the expression and consolidation of the fear and its defensive responses. The main aim of this study was to verify the beta-adrenergic system participation, in the behavior response of rats toward cat odor model. For this purpose, firstly we have realized the biological and pharmacological validation of the cat odor model in accordance to the experimental conditions of our laboratory. Next, the role of central and peripheral beta-adrenergic neurotransmission in rats submitted to this model was evaluated. Whereas propranolol was used to block beta-adrenoceptor at central and peripheral sites of action, nadolol, did it predominantly at the peripheral system. Finally, we have checked the noradrenergic involvement of the PMd - a hypothalamic structure that takes part in the innate defensive behavior - in the defensive response of rats exposed to cat odor, using atenolol, a selective beta1-blocker, microinjected directly into this structure. Our results demonstrate that either propranolol systemic injection or atenolol microinjections into PMd, were able to reduce the defensive behavior of rats exposed to cat odor. These findings suggest a central beta-adrenergic system participation in the innate defensive behavior toward cat odor strengthening the key role of the PMd on this behavior.

One of the most important areas of society-wide tasks influencing the health of the whole population is child care. It includes care of children with a hemangioma. Hemangiomas are the most common benign (not malignant) vascular tumours of a child age. This benign tumour may be present as early as at birth or appear in the first weeks of life. It is usually located on or under the skin surface but may also affect internal organs. Although a hemangioma may affect any body part, it is mostly located on the head and neck. A hemangioma is diagnosed in a tenth of new-born children. Hemangiomas typically appear at neonatal age or infancy. The objectives of the diploma thesis "Nurse's Roles in Care of a Child Patient with a Hemangioma" are to examine the roles of nurses in care of a child patient with a hemangioma, as seen by parents (mothers) of the children, and to identify which of the roles is the most important for the parents (mothers). It has also been ascertained whether nurses deal with any problems while providing this care and whether occurrence of a hemangioma in a child has any influence on the child's family. It has also been ascertained whether any complications are encountered in the treatment of children with a hemangioma. A qualitative research was used for data processing. Several methods of data collection were used. The researcher used a case history according to the model of Virginia Henderson, semi-structured interview with mothers of patients, data content analysis and secret participant observation during outpatient checks. The last method used was a survey aimed at nurses who took care of children with a hemangioma, asking them whether they dealt with any problems and complications in such children. The first research set consisted of ten child patients who were selected on purpose on the basis of pre-set criteria. The first criterion was presence of a hemangioma; five patients were hospitalised with a hemangioma and underwent a treatment with propranolol, while the other five patients with a hemangioma underwent only a conservative treatment. Last but the most important criterion was that mothers of patients with a hemangioma granted their consent to the research. These mothers formed the second research set and underwent a semi-structured interview focused on their personal experience with a hemangioma and on the work of nurses as seen by mothers. The last research set consisted of ten nurses who were also selected on purpose on the basis of a very important criterion, which was care of child patients with a hemangioma. This thesis may be of a benefit not only for professionals who are in contact with children with a hemangioma but may also serve to deepen general knowledge of other healthcare professionals who may encounter this disease either in their professional or private life. Based on the information acquired for the diploma thesis, was prepared for nurses and will be presented at professional workshops.

Made available in DSpace on 2016-06-02T20:34:10Z (GMT). No. of bitstreams: 1 2560.pdf: 1909631 bytes, checksum: 34db098669e19b9e74332c54f977cc2a (MD5) Previous issue date: 2009-08-12 / Financiadora de Estudos e Projetos / The development of electroanalytical procedures for acetylsalicylic acid (ASA), propranolol (PROP), atenolol and sildenafil (Viagra®) in pharmaceutical formulations using a boron doped diamond (BDD) electrode, square wave and differential pulse voltammetric techniques are described. ASA was directly determined in a 0.01 mol L-1 H2SO4 solution without the need of a previous alkaline hydrolysis step with the BDD electrode and square wave voltammetry (SWV). The analytical curve was linear in the ASA concentration range 2.5 × 10-6 to 1.0 × 10-4 mol L-1 with a detection limit of 2.0 × 10-6 mol L-1. Then, the analytical determination of PROP was carried out in a 0.1 mol L-1 H2SO4 solution using a cathodically pre-treated BDD electrode employing SWV. The analytical curve was linear in the PROP concentration range 2.0 × 10-7 to 9.0 × 10-6 mol L-1 with a detection limit of 1.8 × 10-7 mol L-1. The determination of atenolol was accomplished in 0.5 mol L-1 NaNO3 (pHcond 1.1 adjusted with concentrated HNO3) on a cathodically pre-treated BDD electrode employing SWV. The analytical curve was linear in the atenolol concentration range from 2.0 × 10-6 to 4.1 × 10-5 mol L-1 with a detection limit of 9.3 × 10-7 mol L-1. Finally, a procedure for the determination of sildenafil in 0.1 mol L-1 H2SO4 on a cathodically pre-treated BDD electrode employing differential pulse voltammetry was developed. The analytical curve was linear in the sildenafil concentration range 7.3 × 10-7 to 7.3 × 10-6 mol L-1 with a detection limit of 4.8 × 10-7 mol L-1. / Neste trabalho, descreve-se o desenvolvimento de procedimentos eletroanalíticos para a determinação de ácido acetilsalicílico (AAS), propranolol (PROP), atenolol e sildenafila (Viagra®) em formulações farmacêuticas utilizando um eletrodo de diamante dopado com boro (BDD) e as técnicas voltamétricas de onda quadrada e pulso diferencial. O AAS foi determinado diretamente em H2SO4 0,01 mol L-1, sem a necessidade da etapa de hidrólise alcalina, com um eletrodo de BDD e voltametria de onda quadrada (SWV). A curva analítica foi linear no intervalo de concentração de AAS de 2,5 × 10-6 a 1,0 × 10-4 mol L-1, com limite de detecção de 2,0 × 10-6 mol L-1. Na sequência, a determinação do propranolol foi realizada em H2SO4 0,1 mol L-1 sobre o eletrodo de BDD pré-tratado catodicamente empregando a SWV. A curva analítica foi linear no intervalo de concentração de propranolol de 2,0 × 10-7 a 9,0 × 10-6 mol L-1, com limite de detecção de 1,8 × 10-7 mol L-1. Ademais, a determinação do atenolol foi realizada em NaNO3 0,5 mol L-1 (pHcond 1,1 ajustado com HNO3 concentrado) sobre o eletrodo de BDD pré-tratado catodicamente empregando a SWV. A curva analítica foi linear no intervalo de concentração de atenolol de 2,0 × 10-6 a 4,1 × 10-5 mol L-1, com limite de detecção de 9,3 × 10-7 mol L-1. Finalmente, foi desenvolvido um procedimento para a determinação do sildenafila em H2SO4 0,1 mol L-1 sobre o eletrodo de BDD prétratado catodicamente empregando a voltametria de pulso diferencial. A curva analítica foi linear no intervalo de concentração de sildenafila de 7,3 × 10-7 a 7,3 × 10-6 mol L-1, com limite de detecção de 4,8 × 10-7 mol L-1.

Submitted by Caroline Falcao (caroline.rfalcao@ufpe.br) on 2017-06-07T17:41:34Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) 2012-Tese-ValdereicePereiraBaydum.pdf: 1681832 bytes, checksum: b5c9d3beb02641d325fe71ba0c2037f2 (MD5) / Made available in DSpace on 2017-06-07T17:41:34Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) 2012-Tese-ValdereicePereiraBaydum.pdf: 1681832 bytes, checksum: b5c9d3beb02641d325fe71ba0c2037f2 (MD5) Previous issue date: 2012-11-23 / A ocorrência de fármacos no meio ambiente tem se tornado um assunto de interesse nos últimos anos. Grande número desses compostos tem sido detectado em efluentes de estações de tratamento de esgoto (ETE) municipais, águas superficiais e, menos frequentemente, em águas subterrâneas e água potável em todo o mundo. Alguns dos efeitos adversos causados por fármacos incluem toxicidade aquática, desenvolvimento de resistência em bactérias patogênicas, genotoxicidade, e desregulação endócrina. Diferentes fontes podem ser indicadas para explicar o aparecimento de fármacos no ambiente aquático. Atualmente, é amplamente reconhecido que a principal fonte de poluição são os efluentes de ETE. Portanto, o descarte de resíduos farmacêuticos nos efluentes de ETE deve ser minimizado o máximo possível. A remoção de poluentes orgânicos recalcitrantes como fármacos na água e em efluentes pode ser obtida utilizando processos oxidativos avançados (POA). O objetivo deste trabalho é avaliar a eficiência de remoção de Propranolol por meio de POA, avaliar a toxicidade dos produtos de degradação durante os tratamentos bem como realizar um estudo cinético de degradação do composto. O fármaco usado neste estudo foi o Propranolol fornecido pelo LAFEPE. Foi utilizada solução modelo a 20 mgL-1 . Os tratamentos por meio de POA (H2O2/UV, Fenton e foto-Fenton) além de radiação UV (fotólise) e H2O2 foram realizados em escala laboratorial em um reator ao longo de 60 minutos. A radiação UV foi obtida por uma lâmpada a vapor de mercúrio de média pressão de 30 W. A agitação do sistema foi feita utilizando um agitador magnético. Sulfato ferroso heptahidratado foi utilizado como fonte de íons de ferro para o processo Fenton e foto-Fenton. A determinação e a quantificação do fármaco após tratamento por POA, foram realizadas em um espectrofotômetro UV-Vis. Em relação aos resultados obtidos pelo tratamento utilizando POA, o propranolol se mostrou pouco sensível a oxidação com peróxido de hidrogênio. O tratamento Foto-Fenton apresentou melhor eficiência de remoção e o Fenton o melhor resultado de toxicidade. A cinética de oxidação do fármaco foi discutida e verificou-se que o modelo cinético de pseudo-primeira ordem pode descrever melhor a oxidação do fármaco. As principais vantagens e desvantagens de cada processos e a complexidade de comparação dos vários processos de oxidação foram discutidos. O processo Foto-Fenton foi o que removeu mais de 80% do propranolol a 20 mg L-1 em 15 minutos. / The occurrence of pharmaceuticals in the environment has become a subject of interest in recent years. A vast number of these compounds have been detected in sewage treatment plant (STP) effluents, surface waters and, less frequently, in groundwater and drinking water, all over the world. Some of the adverse effects caused by pharmaceuticals include aquatic toxicity, resistance development in pathogenic bacteria, genotoxicity and endocrine disruption. Different sources can be indicated to explain the appearance of pharmaceuticals in the aquatic environment. Nowadays, it is widely accepted that the main source of pollution are STP effluents. Therefore, the discharge of pharmaceutical residues to the environment in STP effluents should be minimized. Removal of recalcitrant organic pollutants such as pharmaceuticals in water and wastewater can be achieved using advanced treatment technologies such as advanced oxidation processes (AOP). The objective of this study is to evaluate the removal efficiency of Propranolol by AOP to identify the degradation products toxicity as well as to perform a degradation kinetic study of these compounds. The pharmaceutical used in this study was Propranolol were purchased from LAFEPE. The pharmaceutical were spiked daily at a concentration of 20 mgL-1 were treated by AOP. The treatments by AOP (H2O2/UV, Fenton and photo-Fenton) and photolysis (UV radiation) and peroxide, were performed in a reactor along 60 minutes. UV radiation was provided by a medium pressure mercury lamp of 30 W. The agitation of the system was realized by a magnetic bar. Ferrous sulfate heptahydrate was used as source of iron for the Fenton and photo-Fenton process. The determination and quantification of the pharmaceutical present during the treatment by AOP were performed with UV-Vis spectrophotometer. With regard to the results obtained by using AOP treatment, the propranolol was less sensitive to hydrogen peroxide. Despite photo-fenton treatment presented the highest removal efficiency and Fenton the best treatment toxicity. The kinetics of oxidation of propranolol has been discussed and it was found that the pseudo-first order kinetic model can describe the oxidation. The main advantages and disadvantages of each process and the complexity of comparing the various advanced oxidation processes (AOP) was discussed. In the photo-fenton process it was possible to remove more than 80% from propranolol concentration of 20 mg L-1 in 15 minutes.

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T17:00:13Z (GMT). No. of bitstreams: 1 Priviero_FernandaBruschiMarinho_D.pdf: 795971 bytes, checksum: 31832925f74929a1ec175452554f3619 (MD5) Previous issue date: 2006 / Resumo: Os antagonistas de adrenoceptores b são usados com sucesso no tratamento de desordens cardiovasculares, mas os mecanismos de ação destas drogas não são ainda claros. Os objetivos deste trabalho foram: 1) Avaliar os efeitos relaxantes diretos dos ß-bloqueadores atenolol, metoprolol e propranolol em anéis de aorta e de artéria mesentérica de ratos; 2) Avaliar a influência do tratamento com propranolol in vivo sobre a reatividade de anéis de aorta e de artéria mesentérica de ratos tornados hipertensos pelo bloqueio crônico da síntese de óxido nítrico. Foram utilizados ratos Wistar machos (200-250 g) procedentes do CEMIB-UNICAMP. Os animais foram anestesiados com halotano, após o qual a aorta e a artéria mesentérica foram removidas. Anéis de aorta e de artéria mesentérica foram montados em banho para órgãos isolados contendo solução de Krebs (37oC, 95 % O2 / 5% CO2). Os anéis foram ligados a transdutores isométricos, os quais, por sua vez, estavam conectados a um sistema Powerlab® de aquisição de dados. Para atingir o primeiro objetivo, curvas concentração-efeito aos ß-bloqueadores foram construídas em anéis pré-contraídos com fenilefrina, com endotélio íntegro ou removido, na ausência ou na presença de L-NAME, ODQ ou indometacina (inibidores da sintase do óxido nítrico, da guanilil ciclase solúvel e da ciclooxigenase, respectivamente). O DL(±)-propranolol promoveu relaxamento dependente da concentração nos anéis de aorta e de artéria mesentérica, ao passo que o metoprolol e o atenolol causaram discreto ou nenhum relaxamento. Os isômeros S- e R- do propranolol relaxaram ambas as preparações, na mesma magnitude que a mistura racêmica. Estes relaxamentos foram reduzidos após a remoção do endotélio ou adição de L-NAME ou ODQ, mas não foi afetado pela indometacina. Em anéis de aorta e de artéria mesentérica com endotélio íntrego, a incubação com propranolol aumentou os níveis teciduais de GMPc (mas não AMPc). A adição de CaCl2 (1-10 mM) em meio desprovido de cálcio resultou em contração dependente da concentração nos anéis de aorta e de artéria mesentérica. Estas contrações foram significativamente reduzidas na presença do propranolol, e abolidas na presença concomitante de propranolol e nifedipina. Para atingir o segundo objetivo deste estudo, os ratos foram submetidos a tratamento por 4 semanas com L-NAME e/ou propranolol, após o qual a aorta e a artéria mesentérica foram isoladas. Curvas concentração-efeito à acetilcolina, gliceriltrinitrato e ao cloreto de cálcio foram construídas. O tratamento crônico com o L-NAME aumentou a pressão arterial dos animais, sendo este aumento prevenido nos ratos co-tratados com propranolol. O relaxamento induzido pela acetilcolina foi praticamente abolido na aorta e na artéria mesentérica dos animais tratados com L-NAME. No entanto, somente na artéria mesentérica, o propranolol foi capaz de reverter (parcialmente) o relaxamento induzido pela acetilcolina. Esta reversão não foi observada em artéria mesentérica pré-contraída com KCl (80 mM). Na artéria mesentérica (mas não na aorta), o relaxamento induzido pelo gliceriltrinitrato foi potencializado em todos os tratamentos. A contração induzida pelo CaCl2 foi maior nos vasos dos animais tratados com L-NAME, sendo este aumento prevenido nos animais co-tratados com propranolol. Os níveis plasmáticos de nitrito/nitrato e a atividade plasmática da SOD aumentaram no grupo L-NAME, e o co-tratamento com propranolol preveniu este aumento. Em conclusão, nossos resultados mostraram que o propranolol age no músculo liso vascular, promovendo relaxamento através de mecanismo parcialmente dependente do endotélio, aumentando os níveis de GMPc, e através do bloqueio do influxo de cálcio. Na hipertensão arterial induzida pelo L-NAME, o propranolol preservou a função endotelial, associado à liberação de EDHF e/ou prostaciclina. Os efeitos relaxantes do propranolol podem estar contribuindo para os efeitos antihipertensivos deste composto, melhorando a reatividade vascular, principalmente da artéria mesentérica / Abstract: ß-adrenoceptor antagonists are largely and successfully prescribed to patients with arterial hypertension and other cardiovascular diseases, but the exact mechanisms of their long-term antihypertensive effects are not completely understood. The aim of this work was: 1) To evaluate the relaxing effects of the ß-blockers atenolol, metoprolol and propranolol in the rat aortic and mesenteric artery ring; 2) To evaluate the influence of the propranolol, administered chronically, in the aorta and mesenteric arteries reactivity in hypertensive rats induced by chronic blockade of nitric oxide synthase. Male Wistar rats (200-250g) were anaesthetized with halothane and sacrificed. The aortae and the mesenteric artery were excised, cut in rings and mounted in a 10-ml organ bath containing Krebs solution (37oC, 95 % O2 / 5% CO2). Each ring was connected to an isometric transducer which was connected to a data acquisition system Powerlab®. In order to investigate the first aim, concentration-response curves were obtained in aortic or mesenteric rings with intact or denuded endothelium, in the absence or in the presence of L-NAME, ODQ or indomethacin (nitric oxide synthase, guanilyl ciclase and ciclooxygenase inhibitors, respectively). DL(±)-propranolol relaxed, in a concentration-dependent manner, the aortic and the mesenteric rings, while metoprolol and atenolol caused a slight or none relaxation. The S- and R- propranolol isomers relax both preparation, with the same magnitude of racemic mixture. These relaxing effects were reduced after endothelium denudation or in the presence of L-NAME or ODQ, but they were not affected by indomethacin. In intact-endothelium aortic and mesenteric rings, after incubation with propranolol it was seen an increase in the tecidual cGMP (but not cAMP) levels. Addition of the CaCl2 (1-10 mM) in a Ca2+-free medium induced a concentration-dependent contractions of aortic and mesenteric rings. These contractions were significantly reduced in the presence of propranolol and abolished when nifedipine was added concomitantly to propranolol. In order to investigate the second aim of this work, rats were chronically treated with L-NAME and/or propranolol, during 4 weeks, and then, the aortae and the mesenteric artery were isolated. Concentration-response curves for acetylcholine, glyceriltrinitrate and CaCl2 were obtained. Chronic administration of L-NAME increased the mean arterial pressure and this increase was prevented in rats co-treated with propranolol. Relaxing resposes to acetylcholine was abolished in the aortic and mesenteric rings from L-NAME treated rats. However, in the mesenteric arteries, propranolol was able to restore (partially) the relaxing response for acetylcholine. This restoration was not seen when tissues were precontracted with KCl (80 mM). In the mesenteric artery (but not in the aorta), the potency of glyceriltrinitrate-induced relaxation was higher in all treated groups. The contractions induced by CaCl2 were higher in vessels from L-NAME-treated rats and this increase was prevented in vessels from animals co-treated with propranolol. Plasma levels of nitrite/nitrate and SOD activity were reduced L-NAME group, and the co-treatment with propranolol prevented this decrease. In conclusion, our results showed that propranolol acts through the vascular smooth muscle, inducing relaxation by a mechanism which involves the endothelium integrity and increasing cGMP levels and blocking the calcium influx. In the arterial hypertension induced by L-NAME, propranolol improves the endothelial function associated to EDHF or prostacyclin release. The antioxidant or the relaxing effects of the propranolol could be contributing to its antihypertensive effects, improving the vascular reactivity, mainly in the mesenteric artery / Doutorado / Doutor em Farmacologia

No description available.

The circulatory system is one of the first systems that develops during embryogenesis. Angiogenesis describes the formation of blood vessels as a part of the circulatory system and is essential for organ growth in embryogenesis as well as repair in adulthood. A dysregulation of vessel growth contributes to the pathogenesis of many disorders. Thus, an imbalance between pro- and antiangiogenic factors could be observed in infantile hemangioma (IH). IH is the most common benign tumor during infancy, which appears during the first month of life. These vascular tumors are characterized by rapid proliferation and subsequently slower involution. Most IHs regress spontaneously, but in some cases they cause disfigurement and systemic complications, which requires immediate treatment. Recently, a therapeutic effect of propranolol on IH has been demonstrated. Hence, this non-selective β-blocker became the first-line therapy for IH. Over the last years, our understanding of the underlying mechanisms of IH has been improved and possible mechanisms of action of propranolol in IH have postulated. Previous studies revealed that gap junction proteins, the connexins (Cx), might also play a role in the pathogenesis of IH. Therefore, affecting gap junctional intercellular communication is suggested as a novel therapeutic target of propranolol in IH. In this review we summarize the current knowledge of the molecular processes, leading to IH and provide new insights of how Cxs might be involved in the development of these vascular tumors