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Reduced CGP12177 binding to cardiac beta-adrenoceptors in hyperglycemic high-fat-diet-fed, streptozotocin-induced diabetic rats.

Authors: Thackeray, JT  Parsa-Nezhad, M  Kenk, M  Thorn, SL  Kolajova, M  Beanlands, RS  DaSilva, JN 
Citation: Thackeray JT, etal., Nucl Med Biol. 2011 Oct;38(7):1059-66. Epub 2011 Aug 9.
Pubmed: (View Article at PubMed) PMID:21831645
DOI: Full-text: DOI:10.1016/j.nucmedbio.2011.04.002

INTRODUCTION: Abnormal sympathetic nervous system and beta-adrenoceptor (beta-AR) signaling is associated with diabetes. [(3)H]CGP12177 is a nonselective beta-AR antagonist that can be labeled with carbon-11 for positron emission tomography. The aim of this study was to examine the suitability of this tracer for evaluation of altered beta-AR expression in diabetic rat hearts. METHODS: Ex vivo biodistribution with [(3)H]CGP12177 was carried out in normal Sprague-Dawley rats for evaluation of specific binding and response to continuous beta-AR stimulation by isoproterenol. In a separate group, high-fat-diet feeding imparted insulin resistance and a single intraperitoneal injection of streptozotocin (STZ) or vehicle evoked hyperglycemia (blood glucose >11 mM). [(3)H]CGP12177 biodistribution was assessed at 2 and 8 weeks post-STZ to measure beta-AR binding in heart, 30 min following tracer injection. Western blotting of beta-AR subtypes was completed in parallel. RESULTS: Infusion of isoproterenol over 14 days did not affect cardiac binding of [(3)H]CGP12177. Approximately half of rats treated with STZ exhibited sustained hyperglycemia and progressive hypoinsulinemia. Myocardial [(3)H]CGP12177 specific binding was unchanged at 2 weeks post-STZ but significantly reduced by 30%-40% at 8 weeks in hyperglycemic but not euglycemic STZ-treated rats compared with vehicle-treated controls. Western blots supported a significant decrease in beta(1)-AR in hyperglycemic rats. CONCLUSIONS: Reduced cardiac [(3)H]CGP12177 specific binding in the presence of sustained hyperglycemia corresponds to a decrease in relative beta(1)-AR expression. These data indirectly support the use of [(11)C]CGP12177 for assessment of cardiac dysfunction in diabetes.

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RGD ID: 6893641
Created: 2012-09-13
Species: All species
Last Modified: 2012-09-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.