Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia.
Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia.
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DOI：
10.1186/1475-2840-10-75
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发表时间：
2011-08-10
影响因子：
9.3
通讯作者：
Dasilva JN
中科院分区：
文献类型：
--
作者：
Thackeray JT;Radziuk J;Harper ME;Suuronen EJ;Ascah KJ;Beanlands RS;Dasilva JN
糖尿病与心血管功能障碍密切相关，部分原因是交感神经系统信号传导受损。葡萄糖、胰岛素和非酯化脂肪酸是交感神经活动和去甲肾上腺素 (NE) 释放的有效刺激剂。我们假设，在高脂饮食喂养的链脲佐菌素（STZ）大鼠持续高血糖伴胰岛素抵抗模型中，持续高血糖会表现出进行性交感神经功能障碍，同时心肌收缩和/或舒张功能恶化。通过正电子发射断层扫描放射性示踪剂和 NE 类似物 [11C] 间羟基麻黄碱 ([11C]HED) 的生物分布，研究了体内心脏交感神经的完整性。通过超声心动图评估心脏收缩和舒张功能。血浆和心脏 NE 水平以及 NE 再摄取转运蛋白 (NET) 表达作为相关测量进行评估。该动物模型表现出胰岛素抵抗、持续高血糖和进行性低胰岛素血症。持续高血糖 8 周后，与对照组相比，STZ 治疗的高血糖大鼠心肌中 [11C]HED 滞留显着减少 13-25%，但血糖正常大鼠则没有。 NE 再摄取转运蛋白的免疫印迹密度平行降低 17%，心脏和血浆 NE 分别升高 1.2 倍和 2.5 倍，而交感神经密度没有变化。超声心动图未检测到射血分数或面积分数变化。高血糖大鼠的心率降低、二尖瓣减速时间延长以及脉冲波多普勒测量的二尖瓣早期与心房血流速度比升高提示左心室舒张受损。总而言之，这些数据表明，持续高血糖与心肌 NE 含量升高和在没有收缩功能障碍的情况下交感神经系统信号传导失调有关。
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. 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. 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. 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.
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