title: Uptake-1 carrier downregulates in parallel with the beta-adrenergic receptor desensitization in rat hearts chronically exposed to high levels of circulating norepinephrine: implications for cardiac neuroimaging in human cardiomyopathies.
abstract: Imaging techniques have demonstrated in various cardiomyopathies that an altered uptake of radiolabeled norepinephrine (NE) analogs may coexist with beta-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 beta-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 (3)H-NE and (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptakes and uptake-1 carrier density using (3)H-mazindol binding assay. The myocardial beta-adrenergic receptor pathway was assessed in vitro by (3)H-CGP 12177 binding and measurement of adenylyl cyclase activity at baseline and under stimulation.
  
  
  RESULTS
  A 34% decrease in (3)H-NE uptake and a 35% decrease in (123)I-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 beta-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.
  
  
  CONCLUSIONS
  The decrease in myocardial beta-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 beta-adrenergic receptor and uptake-1 carrier sites.
authors.affiliation: Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, Direction des Sciences du Vivant-Commissariat à l'Energie Atomique, Orsay, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Mardon
authors.forename: Olivier
authors.initials: O
authors.lastname: Montagne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Elbaz
authors.forename: Zoulikha
authors.initials: Z
authors.lastname: Malek
authors.forename: André
authors.initials: A
authors.lastname: Syrota
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Randé
authors.forename: Michel
authors.initials: M
authors.lastname: Meignan
authors.forename: Pascal
authors.initials: P
authors.lastname: Merlet
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage; D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012016:Reference Values; D013223:Statistics as Topic
chemical_list: D018759:Adrenergic Uptake Inhibitors; D019275:Radiopharmaceuticals; D011943:Receptors, Adrenergic, beta; D019797:3-Iodobenzylguanidine; D009638:Norepinephrine