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Previous issue date: 2009-08-26 / Obesidade, hipertensão, dislipidemia e diabetes tipo 2 são os principais fatores de risco que caracterizam a síndrome metabólica quando presentes simultaneamente. Com o aumento dos níveis de leptina em quadros de obesidade e a correlação desta patologia com a hipertensão, objetivou-se neste trabalho o estudo das possíveis implicações do hormônio leptina na hipertensão de forma central e periférica e a interação com o principal sistema no controle da pressão arterial (PA), o sistema renina-angiotensina (SRA). Neste trabalho nós mostramos que camundongos com mutação espontânea no gene da leptina, ob/ob, ou no receptor de leptina, db/db apresentam deficiências no controle da PA e ritmo circadiano, alterações no SRA e disfunção autonômica. Em camundongos ob/ob, a atividade da ECA, uma das principais enzimas do SRA, apresentou-se reduzida em condições basais e foi restabelecida após o tratamento agudo com leptina. Cronicamente, a administração de leptina aumentou a atividade dessa enzima e a concentração de fatores que compõem o SRA, como o peptídeo vasoconstritor angiotensina II em camundongos ob/ob. No entanto, não houve aumento da PA. Os camundongos ob/ob apresentaram menor baroreflexo, diminuição da ativação parassimpática e aumento da ativação simpática. Os camundongos db/db também apresentaram o mesmo fenótipo. O tratamento com leptina provocou diminuição do peso e restabeleceu a disfunção autonômica em camundongos ob/ob. Surpreendentemente, o tratamento com enalapril também restabeleceu o tônus autônomo, simpático e parassimpático, assim como o baroreflexo em ob/ob e db/db sugerindo a importância da angiotensina II no controle autônomo concomitante com a ausência na sinalização de leptina. Nossos dados sugerem uma nova interação da via de leptina com o SRA, sendo a angiotensina II um possível fator necessário para a manutenção da ativação autonômica e sobrevivência desses camundongos. / The leptin deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and the renin-angiotensin system (RAS) in the cardiovascular abnormalities observed in obesity using a model lacking leptin. Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here we tried to answer the question whether ACE and leptin could influence blood pressure control being a link between renin-angiotensin system and obesity in ob/ob mice, a model lacking leptin. These mice are obese and diabetic, but have normal 24h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Leptin chronic infusion increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion could restore ACE activity in leptin deficient mice. Moreover, the effect of ACE inhibitor on blood pressure during leptin treatment was not changed in lean, but increased four times in obese mice. In a second part of the study we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of ACE by enalapril treatment had similar effects prior loss of weight. These findings suggest that the RAS is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice. In summary, our findings show that the RAS is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible correlation between RAS and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems and may contribute to clarify the role played by these systems in the pathogenesis of obesity, hypertension, and metabolic syndrome. / TEDE / BV UNIFESP: Teses e dissertações
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.unifesp.br:11600/9878 |
| Date | 26 August 2009 |
| Creators | Hilzendeger, Aline Mourão [UNIFESP] |
| Contributors | Universidade Federal de São Paulo (UNIFESP), Pesquero, João Bosco [UNIFESP] |
| Publisher | Universidade Federal de São Paulo (UNIFESP) |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | 176 p. |
| Source | reponame:Repositório Institucional da UNIFESP, instname:Universidade Federal de São Paulo, instacron:UNIFESP |
| Rights | info:eu-repo/semantics/openAccess |
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