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Calcium dynamics in the failing heart: restoration by -adrenergic receptor blockade

Divisions of ¹Molecular Cardiovascular Biology and ²Cardiology, The Children's Hospital and Research Foundation, Cincinnati 45229; ³Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210; ⁴Cardiovascular Research Institute and Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103; ⁵Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706; and ⁶Research Center, Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8

Submitted 20 May 2002 ; accepted in final form 11 March 2003

Changes in calcium (Ca²⁺) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using -adrenergic receptor antagonists (-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of -blocker treatment on Ca²⁺ 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 -receptor blocker (5 mg · kg^-1 · day^-1 propranolol) for 2 wk. Ca²⁺ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca²⁺ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca²⁺ kinetic measurements of time to peak and time decay of the caffeine-induced Ca²⁺ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA), whereas Na⁺/Ca²⁺ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca²⁺ dynamics occurred within 2 wk of -blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that -adrenergic blockade restores Ca²⁺ dynamics and normalizes expression of Ca²⁺-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.

cardiomyopathy; -adrenergic receptor antagonists; dilated

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