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


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.


CONCLUSIONS
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.
Kenk
Miran
M
National Cardiac PET Centre, Division of Cardiology (Department of Medicine), University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada.
Thackeray
James T
JT
Thorn
Stephanie L
SL
Dhami
Karan
K
Chow
Benjamin J
BJ
Ascah
Kathy J
KJ
DaSilva
Jean N
JN
Beanlands
Rob S
RS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001835:Body Weight; D000242:Cyclic AMP / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography / Q000379:methods; D004809:Ephedrine / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects*; D006352:Heart Ventricles; D009206:Myocardium / Q000473:pathology*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta; D020889:Rolipram / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D011943:Receptors, Adrenergic, beta; C065363:3-hydroxyephedrine; D004317:Doxorubicin; D000242:Cyclic AMP; D004809:Ephedrine; D020889:Rolipram