Submitted by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-06-29T12:59:34Z No. of bitstreams: 1 cp118956.pdf: 11152798 bytes, checksum: 413c607598471e1abd0db7c49883c8ac (MD5) / Approved for entry into archive by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-06-29T13:00:23Z (GMT) No. of bitstreams: 1 cp118956.pdf: 11152798 bytes, checksum: 413c607598471e1abd0db7c49883c8ac (MD5) / Made available in DSpace on 2016-06-29T13:00:23Z (GMT). No. of bitstreams: 1 cp118956.pdf: 11152798 bytes, checksum: 413c607598471e1abd0db7c49883c8ac (MD5) Previous issue date: 2009 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Com o crescente aumento da prevalência mundial de diabetes mellitus, tem-se buscado modelos experimentais para melhor compreensão de sua fisiopatologia e tratamento que atendam de maneira mais adequada à preservação de células beta, proteção de órgãos-alvo e atenuação da aterosclerose. Objetivos: Desenvolver modelo experimental de diabetes mellitus tipo 2 induzido por meio de dieta, e utilizá-lo para examinar os efeitos de um inibidor da enzima conversora de angiotensina (IECA) e de um bloqueador do receptor de angiotensina (BRA) na proteção de órgãos-alvo. Métodos: Coelhos machos Nova Zelândia (n=49) receberam dieta acrescida de banha (10%), sacarose (40%) durante todo o protocolo do estudo além de colesterol (0,5% nos três primeiros meses e 0,1% nos meses subseqüentes). Os animais receberam aleatoriamente: apenas a dieta sem fármacos (G1), olmesartana 5 mg (G2), quinapril 30 mg (G3), ou a combinação de ambos (G4), acrescidos à mesma dieta por seis meses. Foram analisados lípides, frutosamina, glicose e insulina em jejum com cálculo dos índices para resistência à insulina e função de células beta pancreáticas. Foram ainda examinadas as áreas sob as curvas de insulina e glicose, após infusão de glicose intraperitoneal. Angiofluoresceinografias e análises histopatológicas avaliaram lesões em órgãos-alvo. Resultados: Os coelhos ganharam peso, e houve aumento dos níveis de glicose, colesterol total, LDL-C e triglicérides e redução do HDL-C (p <0,05 vs. basal). A frutosamina e o HOMA-IR se elevaram, enquanto houve redução do HOMA-β (p <0,05 vs. basal). Sinais precoces de retinopatia diabética foram observados a partir do terceiro mês, progredindo até o final do experimento (p<0,0005). Lesões ateroscleróticas em aorta, esteatofibrose hepática e infiltrado glomerular de macrófagos constituíram os principais achados histomorfológicos. O bloqueio do sistema renina-angiotensina modificou favoravelmente a glicemia e o HOMA-β (p<0,05) e houve atenuação do número e grau dos microaneurismas pelo tratamento com BRA isoladamente ou combinado com IECA (p<0,05 vs. G1). Conclusões: Nosso modelo reproduziu várias características glucometabólicas do diabetes mellitus tipo 2 humanóide, incluindo déficit de secreção e resistência à insulina. O bloqueio do sistema renina-angiotensina atenuou algumas alterações bioquímicas e as lesões microvasculares em retina. / With the increasing prevalence of diabetes mellitus worldwide, new experimental models are required to better understand the pathophysiology of this disease and to offer therapeutic options that can preserve pancreatic beta-cells, protect target organs and attenuate atherosclerosis. Objective: The aims of this study were to develop an experimental model of type 2 diabetes mellitus induced by diet and assess on this model the effects of an angiotensin-converting enzyme inhibitor (ACEI) and an antagonist of the angiotensin II type1 receptor (AT1R) on target organ protection. Methods: New Zealand male white rabbits (n=49) were fed high-fat/high-sucrose (10/40%) during the study protocol and cholesterol-enriched diet (0.5% in the first three months followed by 0.1% until the end of the study). These animals were randomized to receive: diet alone (G1), olmesartan 5 mg (G2), quinapril 30mg (G3), or combination of both drugs (G4), added to the same diet for six months. Fasting lipids, fructosamine, glucose and insulin, with calculation of insulin resistance and beta-cell function indexes were evaluated. The areas under the curves for glucose and insulin were obtained after intraperitoneal glucose bolus injection. Fluorescein angiography and histopathological analyses were performed to assess target-organs lesions. Results: The animals gained weight, and there were increases in blood glucose, total cholesterol, LDL-C and triglycerides, and decrease in HDL-C (p<0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased, while there was a reduction in the HOMA-β (p<0.05 vs. baseline). Early clinical features of diabetic retinopathy were seen since the third month, progressing up to the end of the experiment (p<0.0005). Aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration were the main histomorphologic findings of this study. The renin-angiotensin system (RAS) blockade favorably modified blood glucose and the HOMA- β (p<0.05) and promoted attenuation of the number and grade of microaneurysms in retina in the group of animals receiving AT1R antagonist or combined therapy with the ACEI (p<0.05 vs. G1). Conclusion: Our model reproduced several glucometabolic characteristics of humanoid type 2 diabetes, including decreased insulin secretion and insulin resistance. The RAS blockade attenuated some biochemical abnormalities and the diabetic retinopathy. / FAPESP: 07/51058-8

Made available in DSpace on 2016-06-02T19:46:20Z (GMT). No. of bitstreams: 1 4811.pdf: 907758 bytes, checksum: 8839b04b7f1af2b8827dda89f65c7929 (MD5) Previous issue date: 2012-12-14 / The host institution is one of the lines of political action to guarantee the rights of children and adolescents, whose character is provisional and exceptional form of transition to reintegration and family or for integration in a foster family. Usually occurs when families are considered unable to provide child care, or when they have behaviors that put at risk the full development of children. Both the removal of the child or adolescent from family and his dismissal of the institution are made by the Government, however, there is a lack of effective public policies and scientific research data that cover the issue of institutional shutdown, more specifically. The present study aimed to: a) describe the process of institutional shutdown according to the opinion of adolescents who lived in a situation of institutional care for an extended period and the leaders; b) describe the operation of a host institution. This was a qualitative, exploratory. The study included two leaders of the two institutions reception and six individuals who remained in a state of Reception beyond the time allowed by law, and who completed two years of majority, including motive, which led to the shutdown. The instruments used for data collection were: Interview Script 1) The characteristics of the host institution and Interview Script 2) Shutdown Institutional, both were applied with the leaders of institutions and even Home, Interview Script 3) The Consequences Off the Institutional conducted with former accepted. The questions of the interview scripts were submitted before the application, the judges pointed suggestions to better understand the context. The application of the interviews took place at different times and places previously chosen by the participants. By means of the instruments were performed quantitative analyzes, obtained from the defined categories, with the main parameter to content analysis. The results indicated that in some respects the institutions surveyed described themselves differently, therefore, had different types of conduct with regard to the implementation of some of its functions, humanization of the shutdown process, preparation gradual for that time, maintenance of family ties, family support for restructuring, encouraging interaction with other families, participation in the services offered by the local community. Other aspects described by the Institutional leaders have been characterized equally and refer to similar residential maintenance of emotional bonds between siblings, attendance at small groups, among others. Most adolescents showed that the shutdown was a moment Institutional permeated by feelings of sadness, fear, insecurity, memories, and the individual is ready or not to experience this moment and its consequences were related to the difficulty in getting a job, live alone, keep themselves financially. It is concluded that there is need for specific policies that cover the issue of Institutional shutdown, to support the teen financially, emotionally, socially, before, during and after this procedure. Still, training for all social actors involved in institutional care situation for better care and understanding of the context. / O acolhimento institucional é uma das linhas de ação política da garantia dos direitos da criança e do adolescente, cujo caráter é provisório e excepcional; forma de transição para reintegração familiar e ou para integração em família substituta. Normalmente ocorre quando as famílias são consideradas sem condições de dar assistência aos filhos, ou seja, quando apresentam comportamentos que colocam em risco o desenvolvimento pleno dos filhos. Tanto o afastamento da criança ou adolescente do convívio familiar quanto o seu desligamento da instituição são realizados pelo Poder Público, porém, observa-se a inexistência de políticas públicas eficazes, bem como dados de pesquisas científicas que abarquem a questão do desligamento institucional, mais especificamente neste estudo. O presente estudo teve como objetivos: a) descrever o processo de desligamento institucional sob a óptica de adolescentes que viveram em situação de acolhimento institucional por um período prolongado e das dirigentes; b) descrever o funcionamento de uma instituição de acolhimento sob a óptica do dirigente da instituição. Tratou-se de uma pesquisa qualitativa, de caráter exploratório. Participaram do estudo duas dirigentes de duas Instituições de Acolhimento e seis indivíduos que permaneceram em situação de acolhimento além do tempo permitido por lei, dois anos e que completaram maioridade, motivo inclusive, que acarretou o desligamento. Os instrumentos utilizados para coleta de dados foram: Roteiro de Entrevista 1) As características da Instituição de Acolhimento e Roteiro de Entrevista 2) O Desligamento Institucional, ambos foram aplicados com os dirigentes das Instituições de Acolhimento e ainda, Roteiro de Entrevista 3) As Conseqüências do Desligamento Institucional realizado com os ex-acolhidos. As perguntas dos roteiros de entrevista foram submetidas, antes da sua aplicação, a juizes que apontaram sugestões para melhor compreensão do contexto. A aplicação das entrevistas ocorreu em momentos distintos e em locais previamente escolhidos pelos participantes. Por intermédio dos instrumentos foram realizadas análises quantitativas, obtidas a partir das categorias definidas, tendo como parâmetro principal a análise de conteúdo. Os resultados indicaram que em alguns aspectos as Instituições pesquisadas se descreveram de forma diferente, pois, apresentaram diferentes tipos de condutas no que se refere à execução de algumas de suas funções, entre estas, humanização do processo de desligamento, preparação gradativa para o referido momento, manutenção dos vínculos familiares, apoio à reestruturação familiar, incentivo à convivência com outras famílias, participação nos serviços oferecidos pela comunidade local. Outros aspectos institucionais descritos pelas dirigentes, se caracterizaram de forma igualitária e se referem à semelhança residencial, manutenção dos vínculos afetivos entre irmãos, atendimento em pequenos grupos, entre outros. A maioria dos adolescentes apontou que o desligamento institucional foi um momento permeado por sentimento de tristeza, medo, insegurança, lembranças, tendo o individuo se preparado ou não para vivenciar este momento e suas conseqüências estavam relacionadas à dificuldade em arrumar emprego, viver sozinho, manter-se financeiramente. Conclui-se que há necessidade de políticas públicas especificas que abarquem a questão do desligamento Institucional, que ampare o adolescente financeiramente, emocionalmente, socialmente, antes, durante e após o referido processo. Indica-se ainda, a necessidade de capacitação para todos os atores sociais envolvidos com situação de acolhimento Institucional para melhor atuação e compreensão do contexto.

<p>Cardiovascular diseases (CVD) and their risk factors remain the leading cause of morbidity and mortality in North America. Food-derived bioactive peptides (BAP) have been shown to play a role in regulating physiological pathways of CVD risk factors including hypertension, diabetes, and chronic inflammation. Common sources of BAP include dairy and plant proteins. In addition to being an alternative protein source, it is now accepted that edible insect proteins can also confer health benefits beyond nutrition. However, as with any novel protein source, allergenicity remains a major concern surrounding edible insect consumption. </p> <p>This dissertation aimed to: 1) Evaluate the bioactive potential of peptides from an edible cricket species and; 2) determine the effects of BAP production methods on immunoreactivity. First, peptide-rich extracts were generated from farmed food-grade crickets via enzymatic hydrolysis techniques with the commercial protease Alcalase™. To measure the <i>in vitro</i> bioavailability, cricket peptides were also subject to simulated gastrointestinal digestion (SGD). Peptides and their digests were tested for relevant bioactivities and active groups were further fractionated by chromatographic methods to identify the major peptides responsible for the bioactivity. When tested for <i>in vitro</i> antihypertensive and anti-glycemic properties, cricket peptides were found to inhibit the activities of angiotensin converting enzyme, dipeptidyl peptidase-4, α-amylase, and α-glucosidase. The anti-inflammatory potential was expounded using RAW-264.7 macrophages and human umbilical vein endothelial cells (HUVEC). Cricket peptides (after SGD) effectively lowered NF-κB, MCP-1, and IL-6 production in cells without affecting their viability. Proteomic analyses identified 18 sequences from the enriched cationic peptide fraction that showed the highest activity. Three novel peptides were identified via molecular docking, as potent ACE-inhibitors and binding was similar to that of the commercial drug captopril. Key binding characteristics included interaction with hydrophobic amino acids (Phe, Pro, Leu) near the C-terminal position and coordination with Zn (II) ions near the ACE active site.</p> <p>Immunological reactivity was measured by IgE-binding from shrimp-allergenic patient sera to antigens present within cricket peptides. Our studies demonstrate that immunoreactivity was impacted by enzymatic hydrolysis, depending on the conditions and heating source used. Tropomyosin (a major shrimp allergen) was extracted from both untreated crickets and protein hydrolysates, and verified as the major reactive protein. Tropomyosin reactivity decreased (under both partial and extensive hydrolysis) or retained (under conditions which prevented epitope cleavage). However, using microwave-assisted enzymatic hydrolysis was effective at decreasing tropomyosin reactivity in all immunoassays tested (IgG and IgE). Proteomic and immunoinformatic analyses revealed prominent allergen binding regions of cricket tropomyosin available for cleavage during enzymatic hydrolysis. Conserved antigen regions showed greater homology with other crustacean species, but not with other well studied allergenic insect proteins (i.e., cockroach). Lastly, LC-MS/MS and FT-Raman spectrometry suggests that reactivity was affected due to distinct epitope cleavage within the protein instead of decreased antigen extractability/solubility. </p> <p>The findings of this dissertation support that edible cricket proteins are a potential source of bioactive peptides for functional food or nutraceutical development. Additionally, using protein extraction methods such as microwave-assisted hydrolysis seems a promising tool for minimizing the immunoreactivity of the allergen present in this edible cricket species.</p>

Trauma-informed care is a relatively new construct in K-12 education, and districts across the United States are seeking avenues to meet the needs of their students. The COVID-19 pandemic elevated the need for districts to develop appropriate supports to address student and adult trauma. Traumatic events can affect a child’s mental, physical, social-emotional, and/or spiritual well-being (Substance Abuse and Mental Health Service Administration, 2011). Furthermore, children with an elevated risk of trauma may not be able to access these supports outside of the school setting (Baweja et al., 2015). Therefore, educational systems need to develop trauma-informed care models for schools that furnish a sense of safety and community so that students receive the necessary support. This evaluation aimed to identify how the moderating factors of district administrators, site administrators, climate and culture, and teacher capacity affect trauma-informed care via a multi-tiered system of support (MTSS) framework. It included a specific focus on Tier 1, universal access, to improve timely support for students. This formative program evaluation explored the impact of the moderating factors through the viewpoint of a newly created conceptual framework. I used qualitative and quantitative data sources to explore the multiple aspects of the phenomenon. The ARTIC-45 provided descriptive statistics about educators’ attitudes toward trauma-informed care. The observational data and analysis of the Panorama Education social-emotional learning (SEL) survey that assessed 3rd-12th students social-emotional well-being provided character to the evaluation. The data analysis yielded inconsistent results. The observational data strongly indicated a trauma-informed environment in which students were given clear expectations and engaged in positive reciprocal interactions with peers and adults. The ARTIC-45 data showed that administrators, teachers, and support staff responded favorably to trauma-informed care approaches. Though statistical significance could not be obtained due to the sample size constraint of being too small, the data provided context to the other data sources. For example, teacher capacity could not be quantified, but the data provided context to the overall staff capacity. The review of the archival and current SEL survey data showed that favorability among domains varied by site and grade level. The variations in students' social-emotional favorability can be related to their lived experiences and it is important to track over time to monitor how experiences, expressions, and feelings change over time. Students' perspectives regarding themselves and their environment differed from the observational data. This indicates that educators should not solely rely on observational data to determine students’ social-emotional well-being. Furthermore, an SEL survey can be used as a tool to understand students’ well-being and thus provide them with timely support. The evaluation determined that district administration, site administration, climate and culture and staff capacity can positively impact a multi-tiered, trauma-informed care environment. In these settings, student behavior and social-emotional well-being is viewed in a healing-centered manner. Districts can create a multi-tiered, trauma-sensitive culture and provide support to enhance teachers’ capacity to implement trauma-informed care, take advantage of administrative influence, develop community partnerships, and create a culture that is open to systematic change.

<p> The development of high-quality screening assays for the identification of biologically active ligands is critical in drug discovery. This thesis is aimed at developing new advances m capillary electrophoresis (CE) for the characterization of the conformational stability and enzymatic activity of protein targets with small molecules. CE provides a convenient platform for unbiased assessment of multiple thermodynamic and kinetic parameters associated with biomolecular interactions involving regulatory protein or isomerase enzymes, where various sample pretreatment steps can be integrated directly in-capillary during analysis. The first two chapters of the thesis (Chapters II, III) outline the development of dynamic ligand exchange-affinity capillary electrophoresis (DLEACE) as a novel strategy for the screening of allosteric ligands based on the differential stability of urea-induced unfolding of various apolholo-protein states of cAMP receptor protein constructs. This work introduced a label-free and multivariate approach for ligand selection based on complementary thermodynamic parameters that allowed for determination of the dissociation constant of protein-ligand interactions over a wide dynamic range (> 10^4, Kd = nM-mM). The subsequent two chapters of the thesis (Chapters IV, V) describe the development of a novel kinetic assay for unbiased characterization of isomerase activity associated with D/L-amino acid metabolism using hydroxyproline epimerase as a model system. Stereoselective resolution of various hydroxyproline isomers was accomplished via off-line or on-line chemical derivatization with dynamic complexation usmg chiral selector(s) in order to screen potential inhibitors for putative epimerase and racemase activity. The integration of both thermodynamic and kinetic strategies for differentiation of mutant from wild-type enzymes was important for revealing the function of a catalytic acid/base cysteine pair in the epimerase active site. Overall, this thesis outlines an integrative framework based on CE for high-quality screening, which is relevant in reducing the high attrition rate of lead candidates in drug development. </p> / Thesis / Doctor of Philosophy (PhD)

The rapid development, approval, and production of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in less than 1 year after the first reports of a new infectious disease was a real game changer, providing 80%–90% efficacy in preventing severe etiopathologies of the coronavirus disease 2019 (COVID-19). These vaccines induce an immune response against the SARS-CoV-2 spike (S) protein located on the surface of the virus particle. Antibodies (Abs) recognizing the S-protein can inhibit binding of the virus via the S-protein to the angiotensin-converting enzyme-2 (ACE-2) receptor expressed on different human cells, especially when these Abs bind to the interaction site, the so-called receptor-binding domain (RBD). We have expressed the RBDs of wild-type SARS-CoV-2 and five variants of concern (VOCs) to test the immune response in people before vaccination with mRNA vaccines BNT162b2 and mRNA-1273 and after up to three vaccinations using in-house ELISA and inhibition assays. The methods of both assays are provided. Both vaccines initiated similarly high IgG titers after two vaccinations against the wild-type and even two VOC-RBDs (alpha and delta) and strongly inhibited the corresponding RBD-ACE-2 binding. The IgG titers and inhibition of ACE-2 binding were lower for beta and gamma RBDs and much lower for omicron RBD. The third vaccination after 6 months strongly increased both the IgG titers and the neutralizing effect against all variants, especially for omicron, leading to 63% ± 13% neutralization potential. Importantly, neutralization linearly increased with the IgG titers.

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Background: Diabetic kidney disease is the leading cause of end-stage renal disease. Administration of ACE inhibitors or/and SGLT2 inhibitors show renoprotective effects in diabetic and other kidney diseases. The underlying renoprotective mechanisms of SGLT2 inhibition, especially in combination with ACE inhibition, are incompletely understood. We used longitudinal intravital microscopy to directly elucidate glomerular hemodynamics on a single nephron level in response to the ACE inhibitor enalapril or/and the SGLT2 inhibitor empagliflozin. Methods: Five weeks after the induction of diabetes by streptozotocin, male C57BL/6 mice were treated with enalapril, empagliflozin, enalapril/empagliflozin or placebo for 3 days. To identify hemodynamic regulation mechanisms, longitudinal intravital multiphoton microscopy was employed to measure single nephron glomerular filtration rate (snGFR) and afferent/efferent arteriole width. Results: Diabetic mice presented a significant hyperfiltration. Compared to placebo treatment, snGFR was reduced in response to enalapril, empagliflozin, or enalapril/empagliflozin administration under diabetic conditions. While enalapril treatment caused significant dilation of the efferent arteriole (12.55 ± 1.46 µm vs. control 11.92 ± 1.04 µm, p < 0.05), empagliflozin led to a decreased afferent arteriole diameter (11.19 ± 2.55 µm vs. control 12.35 ± 1.32 µm, p < 0.05) in diabetic mice. Unexpectedly under diabetic conditions, the combined treatment with enalapril/empagliflozin had no effects on both afferent and efferent arteriole diameter change. Conclusion: SGLT2 inhibition, besides ACE inhibition, is an essential hemodynamic regulator of glomerular filtration during diabetes mellitus. Nevertheless, additional mechanisms—independent from hemodynamic regulation—are involved in the nephroprotective effects especially of the combination therapy and should be further explored in future studies.

An Herzinsuffizienz sind in Deutschland weit mehr als 1 Mio. Menschen erkrankt. Ihre Häufigkeit steigt stetig an. Die Herzinsuffizienz wird als dominierende Herz-Kreislauf-Erkrankung des 21. Jahrhunderts angesehen. Die Hauptursache der Herzinsuffizienz ist die koronare Herzerkrankung besonderes nach stattgehabtem Myokardinfarkt. Sowohl für den akuten Myokardinfarkt als auch für die sich auf dieser Basis entwickelnde Herzinsuffizienz werden Veränderungen im Stoffwechsel der Sauerstoffradikale als pathophysiologisch bedeutsam angesehen. Es wird angenommen, dass als Folge der akuten Myokardischämie oxidativer Stress im Myokard hervorgerufen wird. Dieser kann über die akute Infarktphase hinaus prolongieren. Dadurch werden Mechanismen induziert (Hypertrophie und Apoptose, Störung myokardialer Signaltransduktion), die letztlich zur Herzinsuffizienz führen. Folgerichtig sollten therapeutische Maßnahmen, die zu einer Minimierung von oxidativem Stress führen, protektiv wirken. Im Rahmen dieser Arbeit wurde am Modell des Ligaturinfarktes der Ratte gezeigt, dass es in der Akutphase des Infarktes (30-36 h nach Ligatur) zu gesteigertem oxidativen Stress kommt. Dieser ließ sich anhand gesteigerter myokardialer Konzentration an Lipidperoxiden, die mit einer verminderten Konzentration antioxidativer Enzyme im Herz kombiniert war, dokumentieren. Werden solche Tiere 6 Wochen nach Ligatur untersucht, weisen sie im Herz im Vergleich zu scheinoperierten Tieren eine signifikant erhöhte Konzentration von Lipidperoxiden als Zeichen gesteigerten oxidativen Stresses auf. Parallel dazu werden typische Zeichen einer Herzinsuffizienz (Herzhypertrophie, erhöhter LVEDP, verminderte Kontraktilität) beobachtet. Wurden solche Tiere beginnend nach der akuten Myokardphase mit dem ACE-Hemmer Ramipril und dem Beta-Blocker Metoprolol behandelt - von beiden ist bekannt, dass sie protektiv in den Stoffwechsel der Sauerstoffradikale eingreifen können - wurde ein geringerer myokardialer oxidativer Stress beobachtet, der mit einer verminderten Ausprägung der morphologischen und funktionellen Herzinsuffizienzzeichen einherging. Die kombinierte Gabe von Beta-Blocker und ACE-Hemmer erwies sich dabei sowohl in der Reduktion von oxidativem Stress als auch in ihrem Einfluss auf Herzfunktion und Morphologie den Einzeltherapien überlegen. Als wesentlich für die Reduktion von oxidativem Stress durch Beta-Blockade und ACE-Hemmung wurde die kompensatorische Zunahme des enzymatischen antioxidativen Schutzes im Herz (GSH-Px, SOD) ausgewiesen. / In Germany, more than 1 million people suffer from heart failure and the incidence is continuously growing. Consequently, heart failure is accepted to be the dominant disease of the heart and circulatory system in the 21st century. The main reason for heart failure is coronary heart disease in general, and especially myocardial infarction (MI). Changes in the oxygen radical metabolism are thought to be essential in the pathogenesis of myocardial infarction and heart failure as its important consequence. It is supposed that, as a result of myocardial ischemia, oxidative stress arises in the heart, which can activate and prolong mechanisms (hypertrophy, apoptosis, disturbed signal transduction) well documented to result in heart failure. Consequently, treatment, which reduces the myocardial oxidative stress, should be beneficial. Using the model of ligature infarction in rats, our study shows increased myocardial oxidative stress in the acute phase of MI (30-36 h after ligature) documented by increased concentration of lipid peroxides (LPO) combined with reduced activity of the antioxidative enzymes. When the animals were analyzed 6 weeks after ligature in comparison to sham operated animals, increased oxidative stress and in parallel typical signs for heart failure (myocardial hypertrophy, increased LVEDP, reduced contractility) were observed. Treatment of the animals starting after acute myocardial infarction with the ACE-inhibitor Ramipril and the beta-blocker Metoprolol - both are known to interfere protectively with the oxygen radical metabolism - reduced the myocardial oxidative stress and the morphological and functional signs of failing heart. This effect was most impressive after combined treatment with Metoprolol and Ramipril. The elevated enzymatic antioxidative defense (GSH-Px, SOD) which we found in the heart after beta-blockade and ACE inhibition could be the reason.