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

Divisions of 1 Molecular Cardiovascular Biology and 2 Cardiology, The Children's Hospital and Research Foundation, Cincinnati 45229; 3 Department of Physiology and Cell Biology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210; 4 Cardiovascular Research Institute and Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103; 5 Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706; and 6 Research Center, Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8 Submitted 20 May 2002 ; accepted in final form 11 March 2003 Changes in calcium (Ca 2+ ) 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 Ca 2+ 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. Ca 2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca 2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca 2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca 2+ 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 Ca 2+ -ATPase (SERCA), whereas Na + /Ca 2+ 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 Ca 2+ 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 Ca 2+ dynamics and normalizes expression of Ca 2+ -handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts. cardiomyopathy; -adrenergic receptor antagonists; dilated Address for rep