title: Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia.
abstract: BACKGROUND
  Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.
  
  
  METHODS
  Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.
  
  
  RESULTS
  The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.
  
  
  CONCLUSIONS
  Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.
authors.affiliation: Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, K1Y 4W7, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.forename: Jerry
authors.initials: J
authors.lastname: Radziuk
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Ascah
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Jean N
authors.initials: JN
authors.lastname: Dasilva
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D004452:Echocardiography; D006943:Hyperglycemia / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000009:adverse effects; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013599:Systole / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology*
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D013311:Streptozocin; D009638:Norepinephrine