Alterations of pre- and postsynaptic noradrenergic signaling in a rat model of adriamycin-induced cardiotoxicity

J Nucl Cardiol. 2010 Apr;17(2):254-63. doi: 10.1007/s12350-009-9190-x. Epub 2010 Feb 25.

Abstract

Background: Altered sympathetic nervous system signaling is known to play a role in the cardiotoxicity of the anthracycline chemotherapeutic agents, but the interaction of pre- and postsynaptic function is not well understood.

Methods and results: Our aim was to study the noradrenergic signaling in an established rat model of adriamycin cardiotoxicity (15 mg/kg administered i.p. over 2 weeks) using radiotracers having potential applicability for imaging with positron emission tomography (PET). Ex vivo biodistribution was performed 1 and 3 weeks post-adriamycin treatment with the noradrenaline analogue [(11)C]meta-hydroxyephedrine ([(11)C]HED), beta-adrenergic receptor antagonist [(3)H]CGP12177, and phosphodiesterase-4 inhibitor (R)-[(11)C]rolipram. Cardiac function (echocardiographic parameters) and heart/body weight ratio were not affected. Myocardial retention of [(11)C]HED, [(3)H]CGP12177, and (R)-[(11)C]rolipram were unchanged 1 week post-adriamycin. Compared to controls, 3 weeks post-treatment [(3)H]CGP12177 uptake decreased (left ventricle free wall and septum; P < 0.05), while [(11)C]HED and (R)-[(11)C]rolipram uptake were unaffected. Following acute increase in myocardial noradrenaline levels with desipramine treatment, (R)-[(11)C]rolipram retention increased in the left atrium, right ventricle, left ventricle free wall and septum (P < 0.05) in vehicle-, but not adriamycin-treated animals.

Conclusion: Our results suggest that adriamycin-induced toxicity exhibits no change in presynaptic noradrenaline uptake, but decreased beta-adrenergic receptors in cardiac tissues, supporting a role for PET imaging of noradrenaline signaling in the study of anthracycline cardiotoxicity.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Body Weight
  • Cyclic AMP / metabolism
  • Doxorubicin / toxicity*
  • Echocardiography / methods
  • Ephedrine / analogs & derivatives
  • Ephedrine / pharmacology
  • Heart / diagnostic imaging*
  • Heart / drug effects*
  • Heart Ventricles
  • Myocardium / pathology*
  • Radionuclide Imaging
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta
  • Rolipram / pharmacology
  • Sympathetic Nervous System / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Receptors, Adrenergic, beta
  • 3-hydroxyephedrine
  • Doxorubicin
  • Cyclic AMP
  • Ephedrine
  • Rolipram