The Heart Research Institute, Newtown, New South Wales, Australia.
Department of Physiology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Am J Physiol Endocrinol Metab. 2019 Aug 1;317(2):E388-E398. doi: 10.1152/ajpendo.00051.2019. Epub 2019 Apr 23.
The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed "hypoglycemia-associated autonomic failure" (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250-300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia ( = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia ( = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, < 0.05). Activation of medullary C1 ( = 4; 50 ± 5% vs. control 3 ± 1%, < 0.05) and C3 ( = 4; 45 ± 5% vs. control 4 ± 1%, < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 ( = 4; 12 ± 3%, < 0.05) and C3 ( = 4; 19 ± 5%, < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.
自主神经系统对低血糖反应能力的损害被称为“低血糖相关自主神经衰竭”（HAAF）。这种危及生命的现象是由至少两次最近的低血糖发作引起的，但 HAAF 的病理基础在很大程度上仍然未知。尽管纳洛酮似乎在受控条件下改善了低血糖的代偿反应，但低血糖预防仍然是目前治疗 HAAF 的主要方法。延髓腹外侧（C1）和背内侧（C3）的去甲肾上腺素合成神经元投射到调节外周去甲肾上腺素释放的交感节前神经元亚群。在这里，我们确定了 HAAF 中 C1 和 C3 神经元的激活是否受损，以及低血糖预防或纳洛酮治疗 1 周是否可以恢复 C1 和 C3 神经元的激活并改善 HAAF。使用了 20 只雄性 Sprague-Dawley 大鼠（250-300g）。单次低血糖后，血浆肾上腺素水平显著升高（=4；5438±783pg/ml 与对照 193±27pg/ml，<0.05）。反复低血糖显著降低了随后低血糖时的血浆肾上腺素反应（=4；2179±220pg/ml 与 5438±783pg/ml，<0.05）。单次低血糖后，延髓 C1（=4；50±5%与对照 3±1%，<0.05）和 C3（=4；45±5%与对照 4±1%，<0.05）神经元的激活显著增加。在 HAAF 组中，C1（=4；12±3%，<0.05）和 C3（=4；19±5%，<0.05）神经元的激活显著降低。低血糖预防或纳洛酮治疗并未恢复血浆肾上腺素反应或 C1 和 C3 神经元的激活。因此，反复低血糖降低了介导随后低血糖发作时肾上腺髓质反应的 C1 和 C3 神经元的激活。
