Abstract
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.
- norepinephrine
- uptake-1
- β-adrenergic receptor
- radiolabeled norepinephrine analogs
- MIBG
- hydroxyephedrine
- single-photon imaging
- PET
Footnotes
Received Oct. 22, 2002; revision accepted Mar. 24, 2003.
For correspondence contact: Pascal Merlet, MD, PhD, Service de Médecine Nucléaire, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex, France.
E-mail: pascal.merlet{at}hmn.ap-hop-paris.fr