Background: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. Methods: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats were treated with resveratrol (2.5mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. Results: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. Conclusions: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

Background: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. Methods: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats were treated with resveratrol (2.5mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. Results: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. Conclusions: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.

Background: The rostral ventrolateral medulla (RVLM), location of the sympathetic premotor neurons, plays a pivotal role in central cardiovascular regulation. The peroxisome proliferator-activated receptors-£^ (PPAR£^) agonist is commonly prescribed for the treatment of type II diabetes mellitus by its insulin sensitizing ability. Intriguingly, both animal and human studies revealed that PPAR£^ agonist also possesses blood pressure lowering effect although the underlying mechanism is unknown. We designed a study to evaluate the hypothesis that activation of PPAR£^ in the RVLM mediates the blood pressure lowering effect of PPAR£^ agonist, rosiglitazone. Materials and Methods: The 12-week spontaneously hypertensive rats (SHR) and the age-matched normotensive Wistar Kyoto (WKY) rats were used in this study. Basal systemic arterial pressure (SAP) and heart rate (HR) were measured for one week, followed by oral administration of a synthetic PPAR£^ agonist, rosiglitazone (80 mg/kg/day), or saline for 7 days. The hemodynamic profile was recorded for 4 weeks post treatment. The role of PPAR£^ in the RVLM on blood pressure lowering effect of rosiglitazone was examined by microinjection bilaterally into the RVLM of the PPAR£^ antagonist, GW9662 (5 nmol). In a separated series of experiments, the RVLM of SHR or WKY rats was removed at the end of rosiglitazone or saline treatment. Protein expression of PPAR£\, PPAR£]/£_ or PPAR£^ in the RVLM was analyzed by Western blotting. To ascertain that changes in protein expression are not secondary to perturbation of SAP, expression of PPARs was also examined inSHR that received oral administration of a calcium channel inhibitor, amlodipine (16 mg/kg/day), for 7 days. Results: Compared to saline intake, rosiglitazone significantly lowered the mean SBP (MSBP, 159.2¡Ó9.9 mmHg vs. 139.8¡Ó12.6 mmHg) in SHR, but not WKY rats. This blood pressure lowering effect of rosiglitazone in SHR lasted for at least 10 days post treatment. Rosiglitazone treatment, on the other hand, had no significant effect on HR in SHR or WKY rats. At the end of 7-day treatment, microinjection bilaterally into the RVLM of PPAR£^ antagonist, GW9662 (5 nmol), significantly reversed the blood pressure lowering effect of rosiglitazone in SHR. In addition, protein expression of PPAR£\ or PPAR£^ was significantly upregulated in the RVLM of the SHR but not WKY rats that received rosiglitazone treatment. Oral intake of amlodipine (16 mg/kg/day) for 7 days in SHR significantly lowered MSBP (164.8¡Ó7.7 mmHg to 131.8¡Ó7.8 mmHg), but did not affect protein expression of PPAR£\, PPAR£]/£_ or PPAR£^ in the RVLM of SHR. Conclusion: These results suggest that oral administration of rosiglitazone exerts blood pressure lowering effect via activation of PPARs in the RVLM of SHR. Moreover, upregulation of PPAR£\ or PPAR£^ in the RVLM may underlie the antihypertensive effect of rosiglitazone.

Insulin-like growth factor 1 (IGF-1) was considered as a factor potentially involved in arterial hypertension because of its effects on vascular tone. Several studies have suggested that IGF-1 might play an important role in the cardiovascular system for regulation of blood pressure. Previously, microinjection of insulin into the NTS of rats preceded prominent depressor and bradycardic and activates the PI3K downstream Akt. The aims of this study was to compare the cardiovascular responses induced by IGF-1 and to investigate the mechanisms of IGF-1induced signaling pathway in the nucleus tractus solitarius (NTS) between spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto rat (WKY) at 8/16 weeks old. The results indicate that microinjection of IGF-1 into the NTS of WKY and SHR produced dramatically depressor and bradycardic effects. The cardiovascular effects evoked by IGF-1 are less in SHR than WKY rats. The defect in IGF-1 vascular action is also present in young spontaneously hypertensive rats (age 8 weeks). Pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 significantly attenuated the responses evoked by microinjection of IGF-1 in both SHR and WKY at 8/16 weeks old. Moreover, mitogen-activated protein kinase kinase (p44/p42MAPK) inhibitor PD98059 administration attenuated the cardiovascular effects of IGF-1 in WKY at 8/16 weeks old but had no effect in SHR at age matched. In conclusion, both IGF-1/PI3K and p44/p42MAPK signal transduction pathways are involved in controlling central cardiovascular effects in WKY, whereas PI3K but not p44/p42MAPK signaling pathway is involved in SHR. This different condition suggests that such insensitive pathway may play a causative role in the development of hypertension.

β-Adrenergic signalization plays an important role in heart, regulating cardiac frequency and contractility. It is also involved in development of hypertension and heart hypertrophy. Spontaneous hypertensive rat strain is a common model for human essential hypertension, although the origin of blood pressure abnormalities in SHR remains unknown. Dysfunction in the regulation of fatty acid translocase Cd36 was suggested as a link to development of hypertension in SHR. Transgenic strain SHR-Tg19 (also known as SHR-Cd36) was obtained, harboring a wild type of FAT/Cd36. This thesis aimed to investigate key elements of β-adrenergic signaling in the heart of SHR-Tg19 compared to their SHR controls. Expression and distribution of β1- and β2-ARs were measured using radioligand binding and Western blot analysis along with expression of selected G proteins and expression and activity of adenylyl cyclase. Our experiments showed that there were no significant changes in the Gsα and Giα subunits expressions, along with the amount of β1-AR in both left and right ventricles, according to the Western immunoblotting, but radioligand binding showed an increase in the quantity of β-ARs, particularly β2 subtype. Alongside, an increased expression of β2- ARs was observed in the right ventricle. Different...

Abstract In retrospect, Taiwanese manufacturers have outstanding abilities in production which attracted Western international branding companies to give their orders to Taiwan firms. However, with the emerging countries¡¦ arising made a huge impact toward Taiwan OEM industry. This research is aimed at exploring on the gap analysis and strategies of filling the gap on OEM firms trying to transforming to OBM, and together with exploring on the strategic human resource planning during transforming. This research is mainly through data analysis, case study Company¡¦s interview and the comparison with Benchmark Company to achieve the research purposes. This research selects design industry, and moreover, the case study A company is undergoing this OEM to OBM process, in addition to explore the competencies and together with strategic human resource planning dimensions, and as well as the difficulties they were facing. And then, this research used a benchmark firm, Franz, which is also in design industry to make comparison and to learn from Franz through a dynamic competency view. The main contribution of this study is to explore the issue of competency gap while OEM transformed into OBM firms, and used dynamic competency view to suggest the case studied A company to consider different developing stages while making human resource plan. As for those Taiwanese design and fashion companies who also pursue transforming, this research will bring them great benefits.

Submitted by Ana Paula Macedo (ensino@ioc.fiocruz.br) on 2013-10-03T12:27:08Z No. of bitstreams: 1 Fabiana Gomes da Conceição.pdf: 888216 bytes, checksum: 491e32546fbc26e9a0676bfa0fdea80e (MD5) / Made available in DSpace on 2013-10-03T12:27:08Z (GMT). No. of bitstreams: 1 Fabiana Gomes da Conceição.pdf: 888216 bytes, checksum: 491e32546fbc26e9a0676bfa0fdea80e (MD5) Previous issue date: 2011 / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil / Introdução: A hipertensão arterial é um grande desafio para a saúde pública, e quando não tratada, predispõe à morbidade cardiovascular e morte prematura. É sabido que grande parte do aumento da resistência vascular na hipertensão é determinada no nível microvascular e evidências recentes sugerem que uma redução na densidade capilar pode contribuir significativamente para a elevação da resistência vascular e, conseqüentemente, a pressão arterial, tanto em humanos quanto em animais de experimentação. O Echinodorus grandiflorus (EG), uma planta distribuídas em todo o Brasil, tem sido utilizada na medicina popular para tratar hipertensão e doenças inflamatórias. No entanto, não há estudos farmacológicos sobre os efeitos biológicos do extrato. Objetivos: Investigar os efeitos do extrato hidro-alcóolico de Echinodorus grandiflorus sobre a densidade capilar funcional e estrutural da pele, músculo esquelético e do coração em ratos espontaneamente hipertensos. Métodos: Para tanto, foram utilizados 10 Wistar-Kyoto (WKY) e 40 animais SHR. Os animais foram divididos em 5 grupos que receberam veículo (SHR, o grupo controle hipertensos e Wistar, o grupo controle normotenso) e EG (dose 50 mg/kg, 100 mg/kg e 200 mg/kg) durante 28 dias por gavagem. A pressão arterial sistólica e a freqüência cardíaca foram mensurados semanalmente por pletismografia caudal. A densidade capilar funcional foi avaliada no músculo gracil e da pele da orelha, utilizando videomicroscopia intravital após a injeção intravenosa de fluoresceína acoplado ao dextran. A densidade capilar estrutural foi estudada na musculatura esquelética e do ventrículo esquerdo, utilizando análise histológica com FITC acoplado a lectina griffonia simplicifolia, que pode identificar as células endoteliais. Resultados: O tratamento oral com EG diminuiu a pressão sanguínea sistólica em diferentes doses. O tratamento com o EG nas doses de 100 mg/kg e 200 mg/kg reverteu completamente a rarefação capilar funcional no músculo esquelético e pele (316 ± 60 e 353 ± 93 capilares/mm2; 319 ± 56 e 384 ± 70 capilares/mm2, p <0,05, respectivamente) em relação ao grupo controle hipertensos (231 ± 11 e 248 ± 14 capilares/mm2). A análise histológica mostrou que o grupo SHR apresentaram uma menor relação capilar/fibra no músculo esquelético (WKY + VEI 1,94 ± 0,09 e SHR + VEI 1,46 ± 0,05 capilar/fibra no músculo, P <0,05) e o tratamento com EG reverteu a rarefação capilar estrutural nos animais tratados com a dose de 200 mg/kg. A relação capilar/fibra no ventrículo esquerdo de SHR também foi reduzida (WKY + VEI 0,27 ± 0,08 e SHR + VEI 0,20 ± 0,01, P <0,05). Tratamentos com EG não teve efeito na rarefação capilar estrutura do ventrículo esquerdo. Conclusão: O tratamento crônico com EG foi capaz de reduzir a pressão sistólica e capaz de reverter completamente a rarefação capilar funcional e estrutural, na dose mais alta, em animais espontaneamente hipertensos. / Introduction: Hypertension is a major challenge to public health, and when untreated, predisposes to cardiovascular morbidity and premature death. It is known that most of the increase in vascular resistance in hypertension, cause of damage to target organs is determined in the microvascular level and recent evidence suggests that a reduction in capillary density may contribute significantly to the elevation of vascular resistance and, consequently, the blood pressure both in humans and in animals for experimentation. The Echinodorus grandiflorus (EG), a plant and distributed throughout Brazil, has been used in folk medicine for treating hypertension and inflammatory diseases. However, no pharmacological studies on the biological effects of the extract. Objectives: Investigate the effects of an extract Echinodorus grandiflorus on the structural and functional capillary density of the skin, skeletal muscle and heart in spontaneously hypertensive rats. Methods: For that, we purpose used 10 Wistar-Kyoto (WKY) and 40 SHR animals. The animals were divided into 5 groups that received vehicle (SHR, the hypertensive and Wistar control group, the normotensive control group) and SHR that received different doses of EG (50 mg/kg, 100 mg/kg and 200 mg/kg) for 28 days by gavage. The systolic blood pressure and heart rate were measured weekly by photopletismography. Functional capillary density was evaluated in the gracilis muscle and ear’s skin using intravital videomicroscopy after intravenous injection of fluoresceine coupled to dextran. Structural capillary density was studied in the skeletal muscle and left ventricle using histological analysis with a FITC-conjugated Griffonia simplicifolia I lectin, which can identify endothelial cells. Results: The oral treatment with EG decreased the systolic blood pressure in the different groups. Treatment with EG 100 and EG 200 completely reversed the capillary rarefaction functional in skeletal muscle and skin (316 ± 60 and 353 ± 93 ± capillaries/mm2; 319 ± 56 and 384 ± 70 capillaries/mm2, p <0.05, respectively) compared to the hypertensive group (231 ± 11 and 248 ± 14 capillaries/mm2). Histological analysis showed that SHR had a lower capillary-to-fiber ratio in the skeletal muscle (WKY + VEI 1,94 ± 0,09 and SHR + VEI 1,46 ± 0,05 capillary/fiber muscular, P < 0.05) and EG reversed structural capillary rarefaction in animals treated with a dose of 200 mg/kg. Capillary volume density-to-fiber volume density ratio in the left ventricle of SHR was also reduced (WKY + VEH 0.27 ± 0.08 and SHR + VEH 0.20 ± 0.01, P < 0.05). Treatments with EG had no effect on structural capillary rarefaction. Conclusion: The chronic treatment with EG was able to reduce systolic pressure and able to completely reverse the capillary rarefaction functional and structural, at highest dose, in spontaneously hypertensive animals.

Made available in DSpace on 2015-07-22T20:49:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-01-28 / Introdução: Resistência insulínica (RI) e adiposidade visceral estão envolvidas na fisiopatogenia da Síndrome Metabólica (SM). Tratamento farmacológico da RI pode melhorar anormalidades glicêmicas e níveis pressóricos. Objetivos: Produzir modelo de SM, administrando glutamato monossódico (MSG) a ratos espontaneamente hipertensos (SHR) e analisar efeitos da metformina e pioglitazona sobre pressão arterial de cauda (PAC), peso corporal (PC), metabolismo glicídico (MG), gordura epididimal (GE) e massa ventricular esquerda (VE). Métodos: SHR receberam até 11º dia de vida MSG (SHR-MSG). Controles receberam solução salina (SHR). Parte dos animais dos dois grupos, a partir de 12 semanas, recebeu metformina (SHR-Metformina e SHR-MSG-Metformina) ou pioglitazona (SHR-Pioglitazona e SHR-MSG-Pioglitazona) por 12 semanas. Neste período, acompanhou-se PAC e PC e, ao final, realizado teste de tolerância à glicose oral (TTGO), para medir áreas sob curvas de glicose e insulina (ASCG; ASCI) e índice de sensibilidade insulínica (ISI). Após, mediu-se GE e VE. Resultados: Administração de MSG intensificou RI e aumentou GE, sem alterar PAC. Tratamento com metformina nos dois grupos melhorou sensibilidade insulínica e reduziu GE e PAC. Pioglitazona não alterou PAC nos dois grupos; elevou PC nos SHR- MSG; piorou sensibilidade insulínica nos SHR e reduziu GE nos SHR-MSG. Conclusões: MSG induz obesidade visceral, piora MG e não altera PAC. Metformina melhora MG e reduz PAC; ambas reduzem deposição de GE. Nota-se papel da RI hepática nos distúrbios metabólicos e evidenciam-se efeitos cardiovasculares benéficos da melhor sensibilidade insulínica. Ausência de resposta à pioglitazona nos SHR e SHR-MSG pode ser explicada pela mutação do Cd36 desta cepa. / Background: Insulin resistance and visceral adiposity are key factors regarding metabolic syndrome (MS) physiopathology. Insulin resistance pharmacologic treatment might control diverse factors including glicemic abnormalities and blood pressure. Objectives: To produce MS model through monossodium glutamate (MSG) administration to spontaneously hypertensive rats (SHR) and analyze metformin and pioglitazone effects upon tail pressure, weight, glucose metabolism, epididimal fat (EF) and left ventricular mass weight. Methods: SHR received MSG until 11th day after born (SHR-MSG). Controls received saline (SHR). After 12 weeks, part of the two groups received metformin (SHRMeformin and SHR-MSG-Metformin) or pioglitazone (SHR-Pioglitazone and SHRMSG- Pioglitazone) during 12 weeks. Tail pressure and weight were recorded. After, oral glucose tolerance test (OGTT) was performed and areas under glucose (AUCG) and insulin (AUCI) curves and insulin sensibility index were measured. Following OGTT, EF and ventricular mass were assessed. Results: MSG administration increased insulin resistance and EF deposition without affecting tail pressure. Metformin improved insulin sensibility, reduced epididimal fat content and tail pressure. Pioglitazone didn´t impact upon tail pressure in both groups; increased weight in SHR-MSG; worsened insulin sensitivity in SHR, but decreased visceral fat content in SHR-MSG. Conclusions: MSG induced visceral obesity and worsened glucose metabolism in SHR, without affecting tail pressure. Metformin improved glucose metabolism and reduced tail pressure. Both reduce visceral fat deposition. These data points to hepatic insulin resistance as a key factor in metabolic disturbances and reveal benefical cardiovascular effects. Pioglitazone failure might be explained in SHR and SHR-MSG due to CD36 mutation previously described in this rat strain. / TEDE / BV UNIFESP: Teses e dissertações

abstract: ADHD is a childhood neurobehavioral disorder characterized by inordinate levels of hyperactivity, inattention and impulsivity. The inability to withhold a reinforced response, or response inhibition capacity (RIC), is one aspect of impulsivity associated with ADHD. The first goal of this dissertation was to evaluate the fixed minimum interval (FMI) schedule as a method for assessing RIC. Chapter 2 showed that latencies were substantially more sensitive than FMI-derived estimates of RIC to the effects of pre-feeding and changes in rate and magnitude of reinforcement. Chapter 3 examined the ability of the FMI to discriminate between spontaneously hypertensive rats (SHR), an animal model of ADHD, and Wistar Kyoto (WKY) controls. Results from Chapter 3 showed that RIC was not substantially different between SHR and WKY rats. However, latencies were significantly shorter for SHRs than for WKYs suggesting incentive motivation differed between strains. The second goal of this dissertation was to examine the sensitivity of the SHR to nicotine. ADHD is a risk factor for tobacco dependence. The goal of Chapters 4 and 5 was to determine whether the SHR provided a model of ADHD-related tobacco sensitivity. Chapter 4 examined nicotine's locomotor and rewarding effects in adolescent SHRs using the conditioned place preference (CPP) procedure. SHRs developed CPP to the highest nicotine dose tested and were sensitive to nicotine's locomotor-enhancing properties. WKY controls did not develop CPP to any nicotine dose tested and were not sensitive to nicotine's locomotor properties. However, it is likely that nicotine effects were obscured by a pseudo-conditioning to saline in WKYs. Chapter 5 demonstrated that SHRs were more active than WKYs in the open-field but not in the Rotorat apparatus. Results also showed that SHRs and WKYs were both sensitive to nicotine's locomotor sensitizing effects. However, WKYs were more sensitive than SHRs to nicotine's locomotor suppressing effects. Collectively, results from Chapters 4 and 5 show that SHRs are sensitive to the rewarding and locomotor-enhancing properties of nicotine. However, more research is necessary to confirm that SHRs are a suitable model for studying ADHD-related tobacco use. / Dissertation/Thesis / Doctoral Dissertation Psychology 2015

Essential hypertension is the leading contributor to premature death worldwide. Endoplasmic reticulum (ER) stress has recently been implicated in diseased blood vessels and hypertension. It is unclear whether ER stress is a cause or a consequence of hypertension. We hypothesized that ER stress inhibition would prevent the development of hypertension in the young spontaneously hypertensive rat (SHR) by improving vascular structure and function. The SHR was used as a genetic model of human essential hypertension, and the Wistar Kyoto (WKY) rat as its normotensive control. The first study conducted involved assessing the levels of ER stress in young SHRs, before they developed hypertension. The second study conducted involved treating rats with 1g/kg/day of the sodium salt of 4-phenylbutyric acid (4-PBA) orally for 8 weeks from 5 weeks of age. Blood pressure was measured weekly, noninvasively via radiotelemetry. Mesenteric arteries were collected at sacrifice. Finally, the third study conducted involved treating rats with 1g/kg/day 4-PBA orally for eight weeks from five weeks of age, and then withdrawing the drug for four weeks to determine if drug treatment created a sustained lowering of blood pressure. In the first study, ER stress markers were observed to be significantly increased in the young SHR when compared to the WKY. In the second study, blood pressure was observed to be significantly lower in the 4-PBA-treated SHR groups than in the untreated SHRs. In addition, mesenteric arteries from the 4-PBA treated SHRs had a significant decrease in media/lumen ratio, ER stress marker expressions, as well as improved vasodilatory response to carbachol and reduced contractile responses to phenylephrine. In the third study, 4-PBA was able to keep the blood pressure low for one week after withdrawal, however, blood pressure returned to similar levels as untreated SHRs by the end of three weeks. Overall, ER stress inhibition, via 4-PBA, blunted the development of hypertension in the SHR. / Thesis / Master of Science (MSc)