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

¹ Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, Direction des Sciences du Vivant-Commissariat à l’Energie Atomique, Orsay, France
² Institut National pour la Santé et la Recherche Médicale, Unité 400, Université de Médecine, Créteil, France
³ Fédération de Cardiologie, Centre Hospitalo-Universitaire Henri Mondor-Université Paris XII, Créteil, France
⁴ Service de Médecine Nucléaire, Centre Hospitalo-Universitaire Henri Mondor-Université Paris XII, Créteil, France

Imaging techniques have demonstrated in various cardiomyopathies that an altered uptake of radiolabeled norepinephrine (NE) analogs may coexist with ß-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 ß-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 ß-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 ß-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 ß-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 ß-adrenergic receptor and uptake-1 carrier sites.

Key Words: norepinephrine • uptake-1 • ß-adrenergic receptor • radiolabeled norepinephrine analogs • MIBG • hydroxyephedrine • single-photon imaging • PET

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