Intracardiac Ganglion Neuron Dysfunction in Type 2 Diabetes

Abstract

Reduced cardiac parasympathetic activity is involved in sudden cardiac death and is responsible for high mortality in patients with type 2 diabetes mellitus (T2DM). Nicotinic acetylcholine receptor (nAChR) mediates synaptic transmission in intracardiac ganglion (ICG) and regulates the excitability of postganglionic neurons. We hypothesize that changes in the responsiveness of ICG neuronal excitability and postsynaptic nAChR to nicotine (a nAChR agonist) might be involved in attenuated cardiac vagal tone in type 2 diabetic rats. Type 2 diabetic rats were induced by a combination of both high‐fat diet and low‐dose streptozotocin (30 mg/kg i.p.) injection. As an index of cardiac vagal tone, changes of heart rate in response to vagal efferent nerve stimulation were blunted in T2DM rats, compared to sham rats. In Langendorff‐perfused hearts, there was no significant different on sensitivity of the heart to acetylcholine in sham and T2DM rats. Whole‐cell patch‐clamp data showed that nicotine increases action potential frequency and Ca2+ currents in ICG neurons from sham and T2DM rats, which was completely abolished by hexamethonium (a nAChR antagonist). T2DM reduced the responsiveness of ICG neruonal excitability and Ca2+ channel to nicotine. Additionally, T2DM decreased nAChR currents and sensitivity of the nAChR channel to nicotine in ICG neurons. Data from immunofluorescence staining studies showed that T2DM did not alter the protein expression of nAChR subunits in ICG neurons. These results suggest that the low sensitivity of ICG neurons to nicotine might contribute to impairment of the cardiac vagal activity in T2DM.