Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, Salt Lake City, UT.
Diabetes. 2019 Nov;68(11):2107-2119. doi: 10.2337/db19-0306. Epub 2019 Aug 22.
The contribution of the sympathetic nervous system (SNS) versus the parasympathetic nervous system (PSNS) in mediating fatal cardiac arrhythmias during insulin-induced severe hypoglycemia is not well understood. Therefore, experimental protocols were performed in nondiabetic Sprague-Dawley rats to test the SNS with ) adrenal demedullation and ) chemical sympathectomy, and to test the PSNS with ) surgical vagotomy, ) nicotinic receptor (mecamylamine) and muscarinic receptor (AQ-RA 741) blockade, and ) ex vivo heart perfusions with normal or low glucose, acetylcholine (ACh), and/or mecamylamine. In protocols 1-4, 3-h hyperinsulinemic (0.2 units/kg/min) and hypoglycemic (10-15 mg/dL) clamps were performed. Adrenal demedullation and chemical sympathectomy had no effect on mortality or arrhythmias during severe hypoglycemia compared with controls. Vagotomy led to a 6.9-fold decrease in mortality; reduced first- and second-degree heart block 4.6- and 4-fold, respectively; and prevented third-degree heart block compared with controls. Pharmacological blockade of nicotinic receptors, but not muscarinic receptors, prevented heart block and mortality versus controls. Ex vivo heart perfusions demonstrated that neither low glucose nor ACh alone caused arrhythmias, but their combination induced heart block that could be abrogated by nicotinic receptor blockade. Taken together, ACh activation of nicotinic receptors via the vagus nerve is the primary mediator of severe hypoglycemia-induced fatal cardiac arrhythmias.
交感神经系统 (SNS) 和副交感神经系统 (PSNS) 在介导胰岛素引起的严重低血糖时致命性心律失常中的作用尚不清楚。因此，在非糖尿病 Sprague-Dawley 大鼠中进行了实验方案，以通过）肾上腺髓质切除术和）化学性交感神经切除术来测试 SNS，以及通过）手术迷走神经切断术、）烟碱受体（美加明）和毒蕈碱受体（AQ-RA 741）阻断剂和）离体心脏灌注正常或低糖、乙酰胆碱（ACh）和/或美加明来测试 PSNS。在方案 1-4 中，进行了 3 小时高胰岛素（0.2 单位/公斤/分钟）和低血糖（10-15 毫克/分升）夹闭。与对照组相比，肾上腺髓质切除术和化学性交感神经切除术对严重低血糖期间的死亡率或心律失常没有影响。迷走神经切断术导致死亡率降低了 6.9 倍；分别减少第一和第二度心脏传导阻滞 4.6-和 4 倍；并预防了三度心脏传导阻滞与对照组相比。烟碱受体而非毒蕈碱受体的药理学阻断可预防心律失常和死亡率与对照组相比。离体心脏灌注表明，低血糖或 ACh 单独均不会引起心律失常，但两者的组合可引起心脏传导阻滞，而烟碱受体阻断可消除这种阻滞。综上所述，ACh 通过迷走神经激活烟碱受体是严重低血糖引起致命性心律失常的主要介导者。
