Efeito da terapia com Beta-bloqueadores em camundongos com deleção dos receptores alpha 2A/alpha 2C adrenérgicos / Effects of b- adrenergic antagonist therapy in mice lacking a 2A/a 2C adrenergic receptors

AUTOR(ES)

Jan Barbosa Bartholomeu

DATA DE PUBLICAÇÃO

2006

RESUMO

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

ASSUNTO(S)

genetic modified mice sympathetic hyperactivity insuficiência cardíaca b-bloqueadores camundongos geneticamente modificados ?- adrenergic antagonists hiperatividade simpática heart failure

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