Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus

Abstract

Dexmedetomidine, an α2 adrenergic agonist, is a useful sedative but can also cause significant bradycardia. This decrease in heart rate may be due to decreased central sympathetic output as well as increased parasympathetic output from brainstem cardiac vagal neurons. In this study, using whole cell voltage clamp methodology, the actions of dexmedetomidine on excitatory glutamatergic and inhibitory GABAergic and glycinergic neurotransmission to parasympathetic cardiac vagal neurons in the rat nucleus ambiguus was determined. The results indicate that dexmedetomidine decreases both GABAergic and glycinergic inhibitory input to cardiac vagal neurons, with no significant effect on excitatory input. These results provide a mechanism for dexmedetomidine induced bradycardia and has implications for the management of this potentially harmful side effect.

Adrenergic agonist induces rhythmic firing in quiescent cardiac preganglionic neurons in nucleus ambiguous via activation of intrinsic membrane excitability

“…-receptor agonists inhibit both sEPSCs and sIPSCs (Bateman, Boychuk et al 2012), and 1 receptors inhibit IPSCs (Boychuk, Bateman et al 2011). The 2 receptor agonist clonidine and dexmedetomidine inhibit sIPSC (Philbin, Bateman et al 2010;Sharp, Wang et al 2014). Finally, photostimulation of endogenous adrenergic fibers from locus coeruleus inhibited NAm neuronal discharge by selective augmentation of inhibitory currents (Wang, Pinol et al 2014).…”

“…Adrenergic signaling plays an important role in central autonomic control of NAm cholinergic output by modulating excitatory and inhibitory synaptic transmission, as shown by subtype selective adrenoceptor agonists/antagonists (Philbin, Bateman et al 2010;Boychuk, Bateman et al 2011;Bateman, Boychuk et al 2012;Sharp, Wang et al 2014).…”

“…10 Subtype selective adrenergic agonists/antagonists have been shown to modulate synaptic transmission in cardiac vagal neurons within NAm recorded in neonatal rat brainstem slices (Philbin, Bateman et al 2010;Boychuk, Bateman et al 2011;Bateman, Boychuk et al 2012;Sharp, Wang et al 2014;Wang, Pinol et al 2014). We examined whether such synaptic modulation fully explains the adrenergic activation seen in NAm neurons studied in our preparation from young adult mouse.…”

“…Synaptic activation of NAm neurons is regulated by ionotropic glutamate, GABA and glycine signaling, and this input is influenced by various neuromodulators (Jameson, Pinol et al 2008;Dergacheva, Kamendi et al 2009;Philbin, Bateman et al 2010;Dyavanapalli, Byrne et al 2013;Sharp, Wang et al 2014;Dergacheva, Yamanaka et al 2016). The intrinsic membrane excitability of NAm neurons is also sensitive to neuromodulators, for example, aldosterone in neonatal rat neurons (Brailoiu, Benamar et al 2013).…”

Asystole During Administration of Dexmedetomidine with Spinal Anesthesia: A Case Report

“…Sharp et al, using a whole-cell voltage clamp methodology, showed that dexmedetomidine decreased both GA-BAergic and glycinergic inhibitory input to cardiac vagal neurons but had no significant effect on excitatory input in the rat nucleus ambiguus. 10) This means that decreasing inhibitory neurotransmission to cardiac vagal neurons increases the excitability of parasympathetic neurons, leading in turn to bradycardia. Thus, atropine, as an anticholinergic drug, is effective for the bradycardia induced by dexmedetomidine.…”