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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1596    most recent 00308.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Leosco, D. Articles by Rengo, F. Search for Related Content PubMed PubMed Citation Articles by Leosco, D. Articles by Rengo, F.

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

¹Department of Internal Medicine, Cardiovascular Sciences, and Immunology, University Federico II, Naples, Italy; ²George Zallie and Family Laboratory for Cardiovascular Gene Therapy and Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; ³Salvatore Maugeri Foundation, IRCCS, Telese, Italy; ⁴Department of Experimental Medicine and Excellence Center of Cardiovascular Disease, Second University of Naples, Naples Italy; and ⁵Department of Health Sciences, University of Molise, Campobasso, Italy

Submitted 13 March 2007 ; accepted in final form 29 May 2007

Cardiac -adrenergic receptor (-AR) signaling and left ventricular (LV) responses to -AR stimulation are impaired with aging. It is shown that exercise and -AR blockade have a favorable effect on cardiac and vascular -AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on -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 -AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane -AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac -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 -AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and -AR blockade can similarly ameliorate -AR signaling in the aged heart, leading to improved -AR responsiveness and corresponding LV inotropic reserve.

aging; G-protein-coupled receptor kinase 2; -adrenergic receptor desensitization; heart failure

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