Schmid H, Forman L A, Cao X, Sherman P S, Stevens M J
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0678, USA.
Diabetes. 1999 Mar;48(3):603-8. doi: 10.2337/diabetes.48.3.603.
Heterogeneous myocardial sympathetic denervation complicating diabetes has been invoked as a factor contributing to sudden unexplained cardiac death. In subjects with diabetic autonomic neuropathy (DAN), distal left ventricular (LV) denervation contrasts with preservation of islands of proximal innervation, which exhibit impaired vascular responsiveness. The aims of this study were to determine whether this heterogeneous pattern of myocardial sympathetic denervation occurs in a rat model of diabetes and to explore a potential association with regional fluctuations in myocardial nerve growth factor (NGF) protein. Myocardial sympathetic denervation was characterized scintigraphically using the sympathetic neurotransmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial NGF protein abundance and norepinephrine content after 6 and 9 months in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. In ND rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with ND rats, myocardial [11C]HED retention had declined in the proximal segments of STZ-D rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (P < 0.05). Myocardial norepinephrine content was similar in both ND and STZ-D rats. At 6 months, LV myocardial NGF protein content in STZ-D rats decreased by 52% in the proximal myocardial segments (P < 0.01 vs. ND rats) and by 82% distally (P < 0.01 vs. ND rats, P < 0.05 vs. proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the STZ-D rats by 42% (P < 0.01 vs. ND rats), and LV norepinephrine content and NGF protein were decreased in parallel. Therefore, 6 months of STZ-induced diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of LV NGF protein depletion. It is tempting to speculate that regional fluctuations of NGF protein in the diabetic myocardium contribute to heterogeneous cardiac sympathetic denervation complicating diabetes.
异质性心肌交感神经去神经支配并发糖尿病被认为是导致不明原因心脏性猝死的一个因素。在患有糖尿病性自主神经病变（DAN）的受试者中，左心室（LV）远端去神经支配与近端神经支配岛的保留形成对比，近端神经支配岛表现出血管反应性受损。本研究的目的是确定这种异质性心肌交感神经去神经支配模式是否发生在糖尿病大鼠模型中，并探讨其与心肌神经生长因子（NGF）蛋白区域波动的潜在关联。使用交感神经递质类似物C-11羟基麻黄碱（[11C]HED）通过闪烁显像对心肌交感神经去神经支配进行表征，并与非糖尿病（ND）和链脲佐菌素诱导的糖尿病（STZ-D）大鼠在6个月和9个月后心肌NGF蛋白丰度和去甲肾上腺素含量的区域变化进行比较。在ND大鼠中，未检测到近端与远端心肌中[11C]HED滞留或去甲肾上腺素含量的差异。6个月后，与ND大鼠相比，STZ-D大鼠近端节段心肌[11C]HED滞留仅下降了9%（无统计学意义），而远端心肌下降了33%（P<0.05）。ND和STZ-D大鼠的心肌去甲肾上腺素含量相似。在6个月时，STZ-D大鼠左心室心肌近端节段NGF蛋白含量下降了52%（与ND大鼠相比，P<0.01），远端下降了82%（与ND大鼠相比，P<0.01；与近端节段相比，P<0.05）。到9个月时，STZ-D大鼠近端和远端心肌节段的[11C]HED滞留均下降了42%（与ND大鼠相比，P<0.01），左心室去甲肾上腺素含量和NGF蛋白平行下降。因此，STZ诱导的糖尿病6个月会导致大鼠心脏交感神经去神经支配异质性，最大去神经支配发生在远端，并与左心室NGF蛋白消耗的近端到远端梯度相关。很容易推测，糖尿病心肌中NGF蛋白的区域波动导致了并发糖尿病的心脏交感神经去神经支配异质性。
