Abstract
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 1) adrenal demedullation and 2) chemical sympathectomy, and to test the PSNS with 3) surgical vagotomy, 4) nicotinic receptor (mecamylamine) and muscarinic receptor (AQ-RA 741) blockade, and 5) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2107-2119 |
| Number of pages | 13 |
| Journal | Diabetes |
| Volume | 68 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2019 |
Bibliographical note
Funding Information:Acknowledgments. The authors thank Dr. Phil Cryer and Krishan Jethi from Washington University in St. Louis for assistance with the cardiac catecholamine assays. Funding. The authors acknowledge funding from the National Institutes of Health (grant 5T32-DK-091317 to C.M.R. and grant HL-128752 to D.J.D.), JDRF (grant 3-APF-2017-407-A-N to C.M.R.), and the University of Utah Diabetes and Metabolism Research Center (grant RO1 NS070235 to S.J.F.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.M.R. designed and conducted the experiments and wrote the manuscript. J.B., Y.H., and M.O. conducted the experiments and wrote the manuscript. A.M.H. conducted the experiments. D.J.D. designed the experiments and edited the manuscript. S.J.F. designed the experiments and edited the manuscript. S.F.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this manuscript were presented in abstract form at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22–26 June 2018, and the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 7–11 June 2019.
Publisher Copyright:
© 2019 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
