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

Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H305-15. doi: 10.1152/ajpheart.00425.2002. Epub 2003 Mar 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use*
  • Aniline Compounds / metabolism
  • Animals
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Calcium-Transporting ATPases / metabolism
  • Carrier Proteins / biosynthesis
  • Electrophysiology
  • Fluorescent Dyes / metabolism
  • Heart Failure / drug therapy*
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Homeodomain Proteins / metabolism
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins*
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism
  • Myocardial Contraction / drug effects
  • Myocardium / metabolism
  • Nuclease Protection Assays
  • Patch-Clamp Techniques
  • Propranolol / therapeutic use
  • Ryanodine / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Tropomodulin
  • Ventricular Remodeling / drug effects
  • Ventricular Remodeling / physiology
  • Xanthenes / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Aniline Compounds
  • Carrier Proteins
  • Fluorescent Dyes
  • Homeodomain Proteins
  • Microfilament Proteins
  • Tlx2 protein, mouse
  • Tmod1 protein, mouse
  • Tropomodulin
  • Xanthenes
  • Ryanodine
  • Fluo-3
  • Propranolol
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
  • Calcium