Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

Abstract

BackgroundDiabetes 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.MethodsCardiac 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.ResultsThe 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.ConclusionsTaken 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.

Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform

“…We found RyR phosphorylation at S-2808 was enhanced in HG compared to nonHG (Figures 7A and 7B) as has been reported previously and implicated as a contributor of increased SR Ca 2+ leak in HG [15]. The elevated phosphorylation of RyR S-2808 may result from a moderately elevated adrenergic environment in the myocardium due to reduced reuptake of norepinephrine in sympathetic nerves [42]. …”

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“…Dysregulation of sympathetic nervous system signalling is associated with diabetes mellitus, obesity and cardiovascular disease [36,37] possibly by the increased activation of the sympathetic nervous system by angiotensin II [38,39]. Further, glucose, insulin and NEFA potently stimulate sympathetic activity and noradrenaline release [40]. α-Tocopheryl acetate altered cardiac sympathovagal balance in patients with type 2 diabetes by increasing the highfrequency component, an index of vagal efferent activity, and decreasing the low-frequency component of heart rate variability, an index of vasomotor sympathetic activity [41].…”

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“…This model is seen as increasingly important because, in contrast to genetically generated mouse strains that dominate the experimental literature, it closely resembles the most common human condition, termed sporadic AD. There is now a considerable literature on the use of SZT to establish models of insulin resistance (Blondel and Portha, 1989;Koopmans et al, 2006;Cheng et al, 2010;Thackeray et al, 2011). As reviewed previously (de la Monte and Wands, 2008), these SZT-induced changes could be reduced or prevented by early treatment with peroxisome proliferatoractivated receptor agonists in doses smaller than routinely used to treat diabetes type 2.…”