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

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.

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 [¹¹C]meta-hydroxyephedrine ([¹¹C]HED), β-adrenergic receptor antagonist [³H]CGP12177, and phosphodiesterase-4 inhibitor (R)-[¹¹C]rolipram. Cardiac function (echocardiographic parameters) and heart/body weight ratio were not affected. Myocardial retention of [¹¹C]HED, [³H]CGP12177, and (R)-[¹¹C]rolipram were unchanged 1 week post-adriamycin. Compared to controls, 3 weeks post-treatment [³H]CGP12177 uptake decreased (left ventricle free wall and septum; P < 0.05), while [¹¹C]HED and (R)-[¹¹C]rolipram uptake were unaffected. Following acute increase in myocardial noradrenaline levels with desipramine treatment, (R)-[¹¹C]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.

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