Uptake-1 Carrier Downregulates in Parallel with the β-Adrenergic Receptor Desensitization in Rat Hearts Chronically Exposed to High Levels of Circulating Norepinephrine: Implications for Cardiac Neuroimaging in Human Cardiomyopathies

Journal of Nuclear Medicine

André Syrota¹  Karine Mardon¹  Jean-Luc Dubois-Randé¹  Michel Meignan¹  Pascal Merlet¹  Olivier Montagne¹  Zoulikha Malek¹  Nathalie Elbaz¹ 

关键词: norepinephrine;    uptake-1;    β-adrenergic receptor;    radiolabeled norepinephrine analogs;    MIBG;    hydroxyephedrine;    single-photon imaging;    PET;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Imaging techniques have demonstrated in various cardiomyopathies that an altered uptake of radiolabeled norepinephrine (NE) analogs may coexist with β-adrenergic receptor downregulation, but the relationships between these 2 alterations and their mechanisms remain unclear. The aim of this study was to evaluate the hypothesis of a chronic elevation of circulating NE levels as a mechanism of decreased uptake of radiolabeled NE analogs and reduced β-adrenergic receptor sites in the heart. Methods: Osmotic minipumps containing either NE or NaCl were implanted intravenously in rats for 5 d. The uptake-1 function was assessed in vitro by measuring in excised hearts 3H-NE and 123I-metaiodobenzylguanidine (123I-MIBG) uptakes and uptake-1 carrier density using 3H-mazindol binding assay. The myocardial β-adrenergic receptor pathway was assessed in vitro by 3H-CGP 12177 binding and measurement of adenylyl cyclase activity at baseline and under stimulation. Results: A 34% decrease in 3H-NE uptake and a 35% decrease in 123I-MIBG uptake were found in the hearts of rats infused with the NE pump compared with that of rats infused with saline solution (P < 0.05 for both). Moreover, the uptake-1 carrier protein density was decreased by 29% (P < 0.05) and 33% (P < 0.05) in right and left ventricles, respectively, of rats infused with NE compared with those infused with saline solution. Myocardial β-adrenergic receptor desensitization was associated with a 36% reduction in receptor density in the right ventricle (P < 0.05) and a 31% reduction in the left ventricle (P < 0.05) of rats infused with NE compared with those infused with saline solution. Conclusion: The decrease in myocardial β-adrenergic receptors and radiolabeled NE analog uptake found in different cardiomyopathies using neuroimaging techniques may be related to a functional mechanism of NE-induced downregulation of both β-adrenergic receptor and uptake-1 carrier sites.

【 授权许可】

Unknown