Abstract 20105: Sympathetic Nervous Dysregulation Without Systolic Dysfunction in a Rat Model of Insulin Resistance with Sustained Hyperglycemia
Chronic diabetes and insulin resistance are associated with cardiovascular disease and dysregulation of cardiac sympathetic nervous system (SNS) characterized by persistent elevation of plasma and cardiac norepinephrine (NE). These SNS signaling abnormalities may represent a mechanistic link in the development of cardiovascular disease in diabetes. This study evaluates the interaction of hyperglycemia with cardiac health and SNS function in type 2 diabetes. Male Sprague Dawley rats, rendered insulin resistant by high fat feeding and diabetic by a single moderate dose of streptozotocin, were stratified to STZ-treated hyperglycemic (blood glucose >12 mM; n=54), STZ-treated euglycemic (n=36) and vehicle-treated controls (n=37). Cardiac function was serially tested using echocardiography. Sympathetic innervation was assessed at 8 weeks by ex vivo biodistribution of NE analogue [11C]meta-hydroxyephedrine (HED) and by Western blot of NE transporter (NET). Plasma and cardiac NE levels were measured by high performance liquid chromatography with electrochemical detection. Cardiac systolic function was unchanged in hyperglycemic versus controls (64±5 vs 63±2% LVEF). Hyperglycemic rats showed reduced heart rates (276±10 vs 370±39 bpm), prolonged mitral valve deceleration times (31±6 vs 18±5 s), and elevated early to atrial mitral flow velocity ratios (1.8±0.3 vs 1.5±0.3) compared to controls, suggesting diastolic impairment. Sympathetic nervous integrity in hyperglycemic but not euglycemic rats was reduced by 15–20% in cardiac regions as measured by HED biodistribution, paralleled by a 10% reduction in immunoblot density for NET and a 20% elevation of cardiac NE (Table). Taken together, these data suggest that sustained hyperglycemia evokes elevated NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment. Modulation of SNS signaling in diabetes may have beneficial effects for the myocardium.
- © 2010 by American Heart Association, Inc.