TY - JOUR
T1 - Exercise training and β-blocker treatment ameliorate age-dependent impairment of β-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation
AU - Leosco, Dario
AU - Rengo, Giuseppe
AU - Iaccarino, Guido
AU - Filippelli, Amelia
AU - Lymperopoulos, Anastasios
AU - Zincarelli, Carmela
AU - Fortunato, Francesca
AU - Golino, Luca
AU - Marchese, Massimo
AU - Esposito, Giovanni
AU - Rapacciuolo, Antonio
AU - Rinaldi, Barbara
AU - Ferrara, Nicola
AU - Koch, Walter J.
AU - Rengo, Franco
PY - 2007/9
Y1 - 2007/9
N2 - Cardiac β-adrenergic receptor (β-AR) signaling and left ventricular (LV) responses to β-AR stimulation are impaired with aging. It is shown that exercise and β-AR blockade have a favorable effect on cardiac and vascular β-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on β-AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12 wk treadmill training), metoprolol (250 mg·kg-1·day-1 for 4 wk), and exercise plus metoprolol treatment protocols. Ten male Wistar-Kyoto sedentary young rats were also used as a control group. Old trained, old metoprolol-treated, and old trained plus metoprolol-treated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to β-AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane β-AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac β-AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-protein-receptor kinase 2 levels were not upregulated in untrained old compared with young control rats, both exercise and metoprolol treatment resulted in a dramatic reduction of G-protein-receptor kinase 2 protein levels, which is a further indication of β-AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and β-AR blockade can similarly ameliorate β-AR signaling in the aged heart, leading to improved β-AR responsiveness and corresponding LV inotropic reserve.
AB - Cardiac β-adrenergic receptor (β-AR) signaling and left ventricular (LV) responses to β-AR stimulation are impaired with aging. It is shown that exercise and β-AR blockade have a favorable effect on cardiac and vascular β-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on β-AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12 wk treadmill training), metoprolol (250 mg·kg-1·day-1 for 4 wk), and exercise plus metoprolol treatment protocols. Ten male Wistar-Kyoto sedentary young rats were also used as a control group. Old trained, old metoprolol-treated, and old trained plus metoprolol-treated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to β-AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane β-AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac β-AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-protein-receptor kinase 2 levels were not upregulated in untrained old compared with young control rats, both exercise and metoprolol treatment resulted in a dramatic reduction of G-protein-receptor kinase 2 protein levels, which is a further indication of β-AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and β-AR blockade can similarly ameliorate β-AR signaling in the aged heart, leading to improved β-AR responsiveness and corresponding LV inotropic reserve.
KW - β-adrenergic receptor desensitization
KW - Aging
KW - G-protein-coupled receptor kinase 2
KW - Heart failure
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U2 - 10.1152/ajpheart.00308.2007
DO - 10.1152/ajpheart.00308.2007
M3 - Article
C2 - 17557919
AN - SCOPUS:34548461690
VL - 293
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 3
ER -