Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Mediated by the Parasympathetic Nervous System in Rats

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.

Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

“…The healthy minipigs used in this study had a lower fasting blood glucose than what has been reported in studies using commercial pig breeds 33 , rats 15 and in healthy humans 34 , prompting a need for a quite low plasma glucose target to achieve hypoglycaemia with clinical signs. In this study, all minipigs displayed signs of fatigue during hypoglycaemia in the clamp setup, and some even signs of neuroglycopenia, such as myoclonic activity and ataxia 35 , some of which has been described in rat studies 14,15 but not in a previous study of hyperinsulinaemic hypoglycaemia in awake pigs 33 . Though the clamp approach seems to be the better option to reliably induce hypoglycaemia to a specific target in both healthy and diabetic pigs, the single insulin bolus might reflect the clinical setting more closely, where patient's insulin requirements and insulin delivery might not always match 35 .…”

“…However, there are no data to definitely prove causality. In rodents, severe hypoglycaemia induces fatal arrhythmias seemingly mediated by the para-and sympathetic nervous system 14,15 , but the effects of hypoglycaemia has not been well investigated in a large animal model with more human-like anatomy and physiology. The Göttingen minipig is widely used in preclinical research 16 , and their cardiac anatomy and physiology closely resembles that of humans, with cardiac conduction systems and heart size being very similar 17,18 .…”

Temporal Relationship of Glycemia With Cardiac Arrhythmias in Patients With Type 2 Diabetes and CKD

“…1 It is been proposed that hypoglycemia-induced cardiac arrythmias may be one mechanism to explain this relationship. 2 Pre-clinical studies have shown that hypoglycemia leads to upregulation of sympathetic, parasympathetic and inflammatory pathways, 3,4 which promote cardiac irritability. Definitive causal data in humans are limited.…”

Hypoglycaemia and cardiac arrhythmias in diabetes

“…These findings indicate a strong role for the parasympathetic nervous systems as a mediator of cardiac arrhythmias during hypoglycaemic conditions. 22…”