Chronic partial unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in failing rat hearts

J Thorac Cardiovasc Surg. 2009 Feb;137(2):465-70. doi: 10.1016/j.jtcvs.2008.08.033. Epub 2008 Dec 19.

Abstract

Objectives: Mechanical unloading with a left ventricular assist device promotes "reverse remodeling," including restoration of beta-adrenergic receptor signaling and function. We compared the effects of partial unloading and complete unloading on beta-adrenergic responsiveness and gene expressions in failing rat hearts by use of heterotopic heart-lung or heart transplantation models.

Methods: Four weeks after ligation of the left anterior descending artery in Lewis rats, rats with heart failure were divided into 3 groups: infarcted hearts and lungs transplanted into the recipient rats (heart failure-partial unloading, n = 8); infarcted hearts transplanted into the recipient rats (heart failure-complete unloading, n = 7); infarcted (heart failure, n = 8) hearts without transplantation. Normal rats (n = 7) were used as controls. Papillary muscle function and gene expressions were studied at 2 or 4 weeks after transplantation.

Results: In 2-week models, baseline developed tension of papillary muscles significantly increased in heart failure-partial unloading and heart failure-complete unloading compared with heart failure (0.15 +/- 0.07 and 0.12 +/- 0.05 g/mm(2) vs 0.02 +/- 0.01 g/mm(2), P < .05). However, in 4-week models, they decreased to 0.11 +/- 0.03 and 0.10 +/- 0.03 g/mm(2). In 4-week but not in 2-week models, the increase from baseline in baseline developed tension produced by beta-adrenergic stimulation (isoproterenol, 10(-8) and 10(-7) mol/L) was significantly increased in heart failure-partial unloading compared with heart failure-complete unloading and heart failure (P < .05). The mRNA expressions of brain natriuretic peptide and beta(1)- and beta(2)-adrenergic receptors were normalized in both 2- and 4-week models of heart failure-partial unloading.

Conclusions: Chronic partial unloading but not complete unloading improved beta-adrenergic responsiveness and normalized brain natriuretic peptide and beta(1)- and beta(2)-adrenergic receptor mRNA expressions in the failing rat hearts.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology
  • Disease Models, Animal
  • Gene Expression
  • Heart Failure / physiopathology
  • Heart Failure / surgery*
  • Heart Transplantation
  • Heart Ventricles / physiopathology
  • Heart-Lung Transplantation
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • Male
  • Myocardial Contraction / physiology*
  • Myocytes, Cardiac / physiology
  • Natriuretic Peptide, Brain / metabolism
  • Papillary Muscles / physiopathology
  • RNA, Messenger / genetics
  • Rats
  • Rats, Inbred Lew
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism
  • Ventricular Function, Left / physiology*
  • Ventricular Remodeling / physiology

Substances

  • Cardiotonic Agents
  • RNA, Messenger
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Natriuretic Peptide, Brain
  • Isoproterenol