Arginine Vasopressin Alters Both Spontaneous and Phase-Locked Synaptic Inputs to Airway Vagal Preganglionic Neuron via Activation of V1a Receptor: Insights into Stress-Related Airway Vagal Excitation

Abstract

The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) play a major role in the vagal control of tracheobronchial smooth muscle tone and maintenance of airway resistance. The eNA receives vasopressinergic projection from the hypothalamic paraventricular nucleus (PVN), the key node for the genesis of psychological stress. Since airway vagal excitation is reportedly to be associated with the psychological stress-induced/exacerbated airway hyperresponsiveness in asthmatics, arginine vasopressin (AVP) might be involved in stress-related airway vagal excitation. However, this possibility has not been validated. This study aimed to test whether and how AVP regulates AVPNs. In rhythmically active medullary slices of newborn rats, retrogradely labeled AVPNs were identified as inspiratory-activated and inspiratory-inhibited AVPNs (IA- and II-AVPNs) using patch-clamp techniques according to their inspiratory-related firing behavior and synaptic activities. The results show that under current clamp, AVP depolarized both IA- and II-AVPNs, and significantly increased their spontaneous firing rate. Under voltage clamp, AVP elicited a slow inward current, and significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both types of AVPNs. In addition, AVP significantly enhanced the phase-locked excitatory inspiratory inward current in inspiratory-activated airway vagal preganglionic neurons (IA-AVPNs), but significantly suppressed the phase-locked inhibitory inspiratory outward current in II-AVPNs. In both types AVPNs, AVP significantly increased the frequency and amplitude of pharmacologically isolated spontaneous GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs). All of the AVP-induced effects were prevented by SR49059, an antagonist of V1a receptors, but unaffected by SSR149415, an antagonist of V1b receptors. AVP did not cause significant changes in the miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs) and membrane input resistance of either type of AVPNs. These results demonstrate that AVP, via activation of V1a receptors, enhanced the spontaneous excitatory and inhibitory inputs similarly in the two types of AVPNs, but differentially altered their phase-locked inspiratory excitatory and inhibitory inputs. The overall effects of AVP are excitatory in both types AVPNs. These results suggest that increased central AVP release may be involved in the stress-induced augmentation of airway vagal activity, and, consequently, the induction or exacerbation of some airway diseases.

Inspiratory-Activated Airway Vagal Preganglionic Neurones Excited by Thyrotropin-Releasing Hormone via Multiple Mechanisms in Neonatal Rats

“…Blockade of chemical synaptic inputs of the IA-AVPNs could not prevent the TRH-evoked OPs. Nicotine and arginine vasopressin applied to the normally perfused IA-AVPNs enhanced the tonic EPSCs and the inspiratory bursting EPSCs, but did not evoke the OPs ( Zhou et al, 2013 ; Yan et al, 2017 ). These findings suggest that presynaptic inputs are not the underlying cause for the TRH-evoked OP.…”

“…Airway vagal preganglionic neurons have been mainly found in the external compact of nucleus ambiguus (eNA) via application of fluorescent tracer to the extrathoracic tracheal wall ( Haselton et al, 1992 ; Haxhiu and Loewy, 1996 ; Kc et al, 2004 ; Chen Y. et al, 2007 ; Qiu et al, 2011 ; Chen et al, 2012a , b ; Hou et al, 2012 , 2015 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ). AVPNs in the eNA function as the main neurons which modulate cholinergic tone of airway smooth muscles as well as control the intrapulmonary airway resistance and tracheobronchial caliber ( Haselton et al, 1992 ; Canning and Fischer, 2001 ; Yan et al, 2017 ). As shown in previous studies in vivo and in vitro , postganglionic neurons in intrinsic tracheobronchial ganglia have been identified as “phasic” neurons and “tonic” ones, the former firing in phase with inspiration and primarily projecting to tracheobronchial smooth muscles, and the latter firing tonically during expiration and primarily projecting to the intercartilaginous spaces ( Baker, 1986 ; Mitchell et al, 1987 ; Myers et al, 1990 ; Myers, 1998 ).…”

“…As shown in previous studies in vivo and in vitro , postganglionic neurons in intrinsic tracheobronchial ganglia have been identified as “phasic” neurons and “tonic” ones, the former firing in phase with inspiration and primarily projecting to tracheobronchial smooth muscles, and the latter firing tonically during expiration and primarily projecting to the intercartilaginous spaces ( Baker, 1986 ; Mitchell et al, 1987 ; Myers et al, 1990 ; Myers, 1998 ). AVPNs in the eNA also exhibit different rhythmic changes of synaptic inputs in parallel with central inspiratory activities ( Chen Y. et al, 2007 ; Qiu et al, 2011 ; Chen et al, 2012a , b ; Hou et al, 2012 , 2015 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ). Thus, two types of AVPNs are identified according to their different synaptic control during inspiratory phase: some neurons activated by phasic excitatory inputs are identified as IA-AVPNs, and others inhibited by phasic inhibitory inputs are separated as inspiratory-inhibited airway vagal preganglionic neurons (II-AVPNs) ( Chen Y. et al, 2007 ; Qiu et al, 2011 ; Chen et al, 2012a , b ; Hou et al, 2012 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ).…”

“…AVPNs in the eNA also exhibit different rhythmic changes of synaptic inputs in parallel with central inspiratory activities ( Chen Y. et al, 2007 ; Qiu et al, 2011 ; Chen et al, 2012a , b ; Hou et al, 2012 , 2015 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ). Thus, two types of AVPNs are identified according to their different synaptic control during inspiratory phase: some neurons activated by phasic excitatory inputs are identified as IA-AVPNs, and others inhibited by phasic inhibitory inputs are separated as inspiratory-inhibited airway vagal preganglionic neurons (II-AVPNs) ( Chen Y. et al, 2007 ; Qiu et al, 2011 ; Chen et al, 2012a , b ; Hou et al, 2012 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ). Morphological and electrical studies have shown that excitatory and inhibitory synaptic inputs from various brain regions determine the excitability of AVPNs ( Haxhiu et al, 1993 , 2002 , 2003 , 2005 , 2008 ; Kc et al, 2006 ; Wilson et al, 2007 ; Chen et al, 2012b ; Hou et al, 2012 ; Zhou et al, 2013 ; Ge et al, 2015 ; Guo et al, 2017 ; Yan et al, 2017 ), although AVPNs are capable of generating synchronous electrical oscillatory pattern (OP), revealed by “activation of NMDA receptors” or “blockade of GABA A receptors” ( Haxhiu et al, 1987 , 2005 ; Moore et al, 2004 ).…”

Activated Oxytocin Neurons in the PVN-DVC Pathway in Asthmatic Rats

“…Paraventricular hypothalamic nucleus neurons mainly synthesize and secrete oxytocin and arginine vasopressin (AVP) and produce other transmitters ( Japundžić-Žigon et al, 2020 ) such as enkephalin, corticotropin-releasing hormone, thyrotropin-releasing hormone, and cholecystokinin. The central AVP release may be involved in the stress-induced augmentation of airway vagal activity, and, consequently, the induction or exacerbation of some airway diseases ( Yan et al, 2017 ). OT could regulate respiratory and cardiovascular function ( Granjeiro et al, 2014 ) and may act as a potential cardioprotective peptide and improve tachypnea induced by endotoxemia ( Elorza-Ávila et al, 2017 ).…”