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Am J Physiol Heart Circ Physiol (March 20, 2003). doi:10.1152/ajpheart.00425.2002
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Submitted on May 20, 2002
Accepted on March 11, 2003

Calcium Dynamics in the Failing Heart:Restoration by {beta}-Adrenergic Receptor Blockade

David M. Plank1, Atsuko Yatani2, Honda Ritsu2, Sandra Witt3, Betty Glascock3, M.J. Lalli4, Muthu Periasamy4, Celine Fiset5, Nancy Benkusky6, Hector H. Valdivia6, and Mark A. Sussman1*

1 Division of Molecular Cardiovascular Biology, Childrens Hospital Medical Center, Cincinnati, OH, USA
2 Department of Cardiovascular Research Institute, New Jersey Medical School, Newark, NJ, USA
3 Division of Cardiology, Childrens Hospital Medical Center, Cincinnati, OH, USA
4 Department of Physiology and Cell Biology, Ohio State University, Columbus, OH, USA
5 Department of Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
6 Department of Physiology, University of Wisconsin Medical School, Madison, WI, USA

* To whom correspondence should be addressed. E-mail: sussman{at}heart.chmcc.org.

Changes in calcium regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using {beta}-adrenergic receptors antagonists ({beta}-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of {beta}-blocker treatment on calcium dynamics in the failing heart are unknown. To address this issue, tropomodulin overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective {beta}-receptor blocker (propranolol; 5mg/kg/day) for two weeks. Calcium dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared to untreated TOT mice. Frequency-dependent diastolic and calcium transient amplitudes were returned to normal in propranolol treated TOT mice and not untreated TOT mice. Calcium kinetic measurements of time to peak and t50 relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6 fold reduction of sarcoplasmic-reticulum calcium ATPase (SERCA) while sodium-calcium exchanger (NCX) were increased 2.6 fold relative to nontransgenic samples. Propranolol treatment of TOTs reversed the alterations in SERCA and NCX protein levels, but not potassium channels. Although restoration of calcium dynamics occurred within two weeks of {beta}-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took ten weeks to materialize. These results demonstrate that {beta}-adrenergic blockade restores calcium dynamics and normalizes expression of calcium-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.




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