National Cardiac PET Centre, Division of Cardiology (Department of Medicine), University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada.
J Nucl Cardiol. 2010 Apr;17(2):254-63. doi: 10.1007/s12350-009-9190-x. Epub 2010 Feb 25.
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 [(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.
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.
已知交感神经系统信号的改变在蒽环类化疗药物的心脏毒性中起作用，但前突触和后突触功能的相互作用尚不清楚。
我们的目的是使用具有正电子发射断层扫描（PET）成像应用潜力的示踪剂，在阿霉素心脏毒性的已建立大鼠模型中研究去甲肾上腺素能信号（15mg/kg 腹腔注射，持续 2 周）。在阿霉素治疗后 1 周和 3 周，用去甲肾上腺素类似物[（11）C]meta-羟基苯丙胺（[（11）C]HED）、β-肾上腺素能受体拮抗剂[（3）H]CGP12177 和磷酸二酯酶-4 抑制剂（R）-[（11）C]rolipram进行体外生物分布。心脏功能（超声心动图参数）和心脏/体重比不受影响。阿霉素治疗 1 周后，[（11）C]HED、[（3）H]CGP12177 和（R）-[（11）C]rolipram 的心肌保留率不变。与对照组相比，治疗后 3 周，[（3）H]CGP12177 摄取减少（左心室游离壁和室间隔；P < 0.05），而[（11）C]HED 和（R）-[（11）C]rolipram 摄取不受影响。在用去甲丙咪嗪急性增加心肌去甲肾上腺素水平后，（R）-[（11）C]rolipram 在左心房、右心室、左心室游离壁和室间隔的保留增加（P < 0.05）在载体中，但不是在阿霉素处理的动物中。
我们的结果表明，阿霉素诱导的毒性在心肌去甲肾上腺素摄取方面没有变化，但在心脏组织中β-肾上腺素能受体减少，支持使用去甲肾上腺素能信号 PET 成像来研究蒽环类心脏毒性。
