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Am J Physiol Heart Circ Physiol (June 8, 2007). doi:10.1152/ajpheart.00308.2007
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Submitted on March 13, 2007
Accepted on May 29, 2007

EXERCISE AND {beta}-BLOCKER TREATMENT AMELIORATE AGE-IMPAIRED {beta}-ADRENERGIC RECEPTOR SIGNALING AND ENHANCE CARDIAC RESPONSIVENESS TO ADRENERGIC STIMULATION

Dario Leosco1*, Giuseppe Rengo2, Guido Iaccarino1, Amelia Filippelli3, Anastasios Lymperopoulos4, Carmela Zincarelli5, Francesca Fortunato1, Luca Golino6, Massimo Marchese6, Giovanni Esposito7, Antonio Rapacciuolo6, Barbara Rinaldi8, Nicola Ferrara9, Walter J. Koch10, and Franco Rengo7

1 Department of Internal Medicine, Cardiovascular Sciences and Immunology, University Federico II, Napoli, Italy, Napoli, Italy
2 George Zallie and Family Laboratory for Cardiovascular Gene Therapy and, Center for Translational Medicine, Dept. of Medicine, Thomas Jefferson University, Philadelphia, PA, USA, 19107. Salvatore Maugeri Foundation - IRCCS, Telese (BN), Italy, Philadelphia, Pennsylvania, United States
3 Department of Experimental Medicine and Excellence Center of Cardiovascular Disease, Second University of Naples, Italy, Napoli, Italy
4 George Zallie and Family Laboratory for Cardiovascular Gene Therapy and, Center for Translational Medicine, Dept. of Medici, Thomas Jefferson University, Philadelphia, PA, USA, 19107, Philadelphia, Pennsylvania, United States
5 George Zallie and Family Laboratory for Cardiovascular Gene Therapy and, Center for Translational Medicine, Dept of Medicine, University Federico II, Naples, Italy. Thomas Jefferson University, Philadelphia, PA, USA, Philadelphia, Pennsylvania, United States
6 Napoli, Italy; Department of Internal Medicine, Cardiovascular Sciences and Immunology, University Federico II, Napoli, Italy, Napoli, Italy
7 Department of Internal Medicine, Cardiovascular Sciences and Immunology, University Federico II, Napoli, Italy, Napoli, Italy; Napoli, Italy
8 Napoli, Italy; Department of Experimental Medicine and Excellence Center of Cardiovascular Disease, Second University of Naples, Italy, Napoli, Italy
9 Department of Health Sciences, Salvatore Maugeri Foundation - IRCCS, Telese (BN), Italy. University of Molise, Italy, Campobasso, Italy
10 Translational Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: dleosco{at}unina.it.

Cardiac {beta}-adrenergic receptor ({beta}-AR) signaling and left ventricular (LV) responses to {beta}-AR stimulation are impaired with aging. It is shown that exercise and{beta}-AR blockade have a favourable effect on cardiac and vascular {beta}-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on {beta}AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto (WKY) aged rats were randomized to sedentary, exercise (12 wks treadmill training), metoprolol (250 mg/Kg/d for 4 wks), and exercise plus metoprolol treatment protocols. Ten male WKY sedentary young rats were used as control group. Old trained, old metoprolol, and old trained plus metoprolol-treated rats showed significantly improved LV +dP/dt and -dP/dt responses to {beta}-AR stimulation (isoproterenol) compared to old untrained animals. We found a significant reduction in cardiac membrane {beta}AR density and adenylyl cyclase (AC) activity in old untrained animals compared to young rats. Exercise training and metoprolol, alone or combined, restored cardiac {beta}AR density and G-protein dependent AC activation in old rats. Although cardiac membrane G-protein receptor kinase-2 (GRK2) levels were not upregulated in untrained old compared to young rats, both exercise and metoprolol, resulted in a dramatic reduction of GRK2 protein levels, which is a further indication of {beta}AR signaling amelioration in the aged heart induced by these treatments. In conclusion, we demonstrate for the first time that exercise and {beta}-AR blockade can similarly ameliorate {beta}AR signaling in the aged heart leading to improved {beta}AR responsiveness and corresponding LV inotropic reserve.




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