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This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thackeray, J. Articles by Beanlands, R. PubMed Articles by Thackeray, J. Articles by Beanlands, R.

Evaluating presynaptic sympathetic nervous function in adriamycin-induced cardiotoxicity in rats

¹ National Cardiac PET Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; ² School of Medicine, University of Ottawa, Ottawa, Ontario, Canada

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Objectives: The anthracycline antineoplastic agent adriamycin (ADR) has been shown to induce cardiotoxicity, manifested by reduced cardiac function and elevated myocardial norepinephrine (NE) content. [¹¹C]meta-Hydroxyephedrine (HED) is used in cardiac PET as an index of NE reuptake transporter (NET) density and synaptic NE levels. Binding of the labeled NET inhibitor [³H]nisoxetine (NSX) is proportional to NET levels. The aim of this study was to assess in vivo presynaptic sympathetic integrity in ADR-induced cardiotoxicity in rats.

Methods: Male Sprague-Dawley rats were administered 6 injections over 2 weeks of ADR (total 15 mg/kg ip) or saline (CTL) with endpoints at 1 (n=21 ADR, n=10 CTL) and 3 weeks (n=11 ADR, n=8 CTL) after final injection. At this time, rats were injected with either HED or NSX and sacrificed after 30 or 45 min. Heart, skeletal muscle, and blood were counted for radioactivity.

Results: Rats treated with ADR exhibited decreased weight gain and ascites, consistent with ADR-toxicity. Mortality rate was 7% at 1 wk and 33% at 3 wks. At 1 wk, myocardial HED and NSX retention was comparable between ADR and CTL rats. Conversely at 3 wks post-ADR, NSX binding was elevated by 28-45% (p<0.05)in ADR as compared to CTL (left ventricle: 0.65±0.14 vs 0.50±0.06), suggesting upregulated neuronal NET in spite of high NE levels. No comparable change in HED uptake was evident.

Conclusions: These data support a paradoxical increase in NET density in a rat model of ADR toxicity. Lack of an accompanying increase in HED uptake may reflect increased NE content. In light of this observation, HED imaging may not be useful for evaluation of presynaptic sympathetic neuronal function in ADR-induced cardiotoxicity.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thackeray, J. Articles by Beanlands, R. PubMed Articles by Thackeray, J. Articles by Beanlands, R.