Exercise training and Beta-blocker treatment ameliorate age-dependent impairment of Beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation.

Cardiac beta-adrenergic receptor (B-AR) signaling and left ventricular (LV) responses to B-AR stimulation are impaired with aging. It is shown that exercise and B-AR blockade have a favorable effect on cardiac and vascular B-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on B-AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12wk treadmill training), metoprolol (250 mgkg1 day1 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 metoprololtreated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to B-AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane B-AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac B-AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-proteinreceptor 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 -AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and B-AR blockade can similarly ameliorate B-AR signaling in the aged heart, leading to improved B-AR responsiveness and corresponding LV inotropic reserve.