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

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. 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. 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. 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.