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

Introduction: Abnormal sympathetic nervous system and beta-adrenoceptor (beta-AR) signaling is associated with diabetes. [H-3]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 [H-3]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). [H-3]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 [H-3]CGP12177. Approximately half of rats treated with STZ exhibited sustained hyperglycemia and progressive hypoinsulinemia. Myocardial [H-3]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 [H-3]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 [C-11]CGP12177 for assessment of cardiac dysfunction in diabetes. (C) 2011 Elsevier Inc. All rights reserved.