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Master's Dissertation
DOI
10.11606/D.39.2006.tde-07122006-131547
Document
Author
Full name
Jan Barbosa Bartholomeu
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2006
Supervisor
Committee
Brum, Patricia Chakur (President)
Colombo, Fernanda Marciano Consolim
Negrao, Carlos Eduardo
Title in Portuguese
Efeito da terapia com Beta-bloqueadores em camundongos com deleção dos receptores alpha 2A/alpha 2C adrenérgicos
Keywords in Portuguese
b-Bloqueadores
Camundongos geneticamente modificados
Hiperatividade simpática
Insuficiência cardíaca
Abstract in Portuguese
Recentemente foi descrito que a deleção dos receptores a2A e a2C adrenérgicos em camundongos, proporciona hiperatividade simpática com evidências de insuficiência cardíaca (IC) aos sete meses de idade. Com isso, esses animais representam um modelo experimental para o estudo de diferentes terapias da IC. Estudamos o efeito de antagonistas b-adrenérgicos (BB) de diferentes gerações em camundongos deleção para os receptores a2A e a2C adrenérgicos (KO) entre cinco a sete meses de idade que apresentam mortalidade de 50%. Foram utilizados camundongos controle (CO) (n = 22) e KO (n = 94) divididos randomicamente e tratados por dois meses com salina, propranolol (P), metoprolol (M) e carvedilol (C). Foi avaliada a pressão arterial, freqüência cardíaca (FC), além da tolerância ao esforço (TE) e fração de encurtamento (FS) do ventrículo esquerdo. A estrutura cardíaca foi avaliada pelo diâmetro dos cardiomiócitos (DC) e a fração de colágeno cardíaco (CC). Aos sete meses de idade os KO tratados com salina apresentaram intolerância ao esforço e redução de 30% na FS, e aumento do DC (13%) quando comparados com os CO. Todos os BB foram eficientes em reduzir a FC de repouso dos KO que tornaram-se semelhantes as dos CO. Nenhum BB restabeleceu a TE nos animais KO. P, M e C restauraram de forma similar a FS nos KO. Apesar de todos os BB reduzirem DC, apenas M restabeleceu as dimensões dos cardiomiócitos que passaram a ser semelhantes as dos CO. Em contrapartida, apenas M reduziu parcialmente o CC. M e C reduziram a mortalidade dos KO em 31 %, sendo que o tratamento com propranolol reduziu a mortalidade dos KO em apenas 24% e foi o BB menos tolerado. Os dados evidenciam o beneficio de M e C no tratamento da IC, e sugerem maior estudo das propriedades farmacodinâmicas de M sobre o remodelamento cardíaco.
Title in English
Effects of b- adrenergic antagonist therapy in mice lacking a 2A/a 2C adrenergic receptors
Keywords in English
?- Adrenergic antagonists
Genetic modified mice
Heart failure
Sympathetic hyperactivity
Abstract in English
We have recently reported that disruption for both a2A ?and a2C adrenergic receptor subtypes in mice (KO) leads to sympathetic hyperactivity with evidence of heart failure (HF) by the age of 7 months. These mice provide a model system for evaluating the efficiency among different ?- adrenergic antagonists (BB) for HF therapy. In the present study, we evaluate the effect of three different BB in a cohort of a wild type (n=22) control group (WT) and a cohort of congenic KO (n=94) from five to seven mo of age. Mice from both groups were randomly assigned to receive by gavage (seven days/wk) either saline (S), propranolol (P), metoprolol (M), or carvedilol (C). Exercise capacity was measured using a graded treadmill protocol. Blood pressure (BP) and heart rate (HR) were determined by tail cuff and LV function by echocardiography. The cardiomyocyte width (CW) and cardiac collagen content (CC) were evaluated by light microscopy. At seven mo of age, when cardiac dysfunction is severe, KO treated with S displayed exercise intolerance and 30% decrease in fractional shortening (FS) when compared with WT. In addition, CW (13%) was increased. All BB were efficient in reducing baseline HR of KO mice towards WT levels, however P was less tolerated. Again, all BB similarly restored FS, and reduced CW, but only M reduced CW towards WT levels. Only M significantly decreased CC. M and C decreased mortality rate of KO mice (31 %), while P did decrease it in only 24%. Collectively these data provide direct evidence for beneficial effect of M and C in restoring cardiac function. Further investigation is need to better understand the pharmacodynamics of M on cardiac remodeling
 
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ABSTRACT.pdf (15.09 Kbytes)
AGRADECIMENTOS.pdf (14.24 Kbytes)
CAPA.pdf (5.06 Kbytes)
Disserta.pdf (639.50 Kbytes)
FICHAJan.pdf (6.36 Kbytes)
FOLHAROSTO.pdf (7.09 Kbytes)
ListadeSiglas.pdf (9.26 Kbytes)
ListaFiguras.pdf (8.73 Kbytes)
ListaTabelas.pdf (7.34 Kbytes)
RESUMO.pdf (15.96 Kbytes)
Sumario.pdf (13.50 Kbytes)
Publishing Date
2006-12-15
 
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