title: Reduced CGP12177 binding to cardiac β-adrenoceptors in hyperglycemic high-fat-diet-fed, streptozotocin-induced diabetic rats.
abstract: BACKGROUND
  Abnormal sympathetic nervous system and β-adrenoceptor (β-AR) signaling is associated with diabetes. [(3)H]CGP12177 is a nonselective β-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 β-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 β-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 β-AR binding in heart, 30 min following tracer injection. Western blotting of β-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 β(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 β(1)-AR expression. These data indirectly support the use of [(11)C]CGP12177 for assessment of cardiac dysfunction in diabetes.
authors.affiliation: Molecular Function and Imaging Program, National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y4W7.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.forename: Maryam
authors.initials: M
authors.lastname: Parsa-Nezhad
authors.forename: Miran
authors.initials: M
authors.lastname: Kenk
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Thorn
authors.forename: Maria
authors.initials: M
authors.lastname: Kolajova
authors.forename: Rob S B
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Jean N
authors.initials: JN
authors.lastname: DaSilva
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011412:Propanolamines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C033394:CGP 12177