Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade.
Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using beta-adrenergic receptor antagonists (beta-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of beta-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 beta-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 beta-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that beta-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.
Plank
David M
DM
Divisions of Molecular Cardiovascular Biology, The Children's Hospital and Research Foundation, Cincinnati, OH 45229, USA.
Yatani
Atsuko
A
Ritsu
Honda
H
Witt
Sandra
S
Glascock
Betty
B
Lalli
M Jane
MJ
Periasamy
Muthu
M
Fiset
Celine
C
Benkusky
Nancy
N
Valdivia
Hector H
HH
Sussman
Mark A
MA
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D004594:Electrophysiology; D005456:Fluorescent Dyes / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D023282:Nuclease Protection Assays; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000627:therapeutic use; D012433:Ryanodine / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D051348:Tropomodulin; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology; D014966:Xanthenes / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000814:Aniline Compounds; D002352:Carrier Proteins; D005456:Fluorescent Dyes; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; C107836:Tlx2 protein, mouse; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D014966:Xanthenes; D012433:Ryanodine; C059715:Fluo-3; D011433:Propranolol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium