ReviewChemical stimulation of vagal afferent neurons and sympathetic vasomotor tone
Introduction
Afferent nerve fibers that relay information about the status of the cardiovascular system arise from structures in the cardiopulmonary region such as the carotid sinus, the aortic arch and the chambers of the heart. These fibers travel in the carotid sinus nerve, aortic depressor nerve and the cervical vagus nerve [58], [81], [210]. Many of these afferents have specialised peripheral terminations that have mechanoreceptor properties and respond to stretch or distortion of the structures which they innervate. Baroreceptor afferent nerve fibers arising from the carotid sinus and the aortic arch are examples of mechanoreceptors which are activated by stretch or distortion of the wall of the structure in which they occur. The vagus contains mechanosensitive afferent fibers which are predominantly of the C-fiber (un-myelinated) type and arise from mechanoreceptors located in the atria, ventricles, aorta and lungs [38].
Apart from mechanoreceptive afferent nerve fibers, the vagus contains a population of chemosensitive afferent fibers which respond to a range of endogenous molecules including neurotransmitter candidates, sugars, lipids, peptide hormones, prostanoids, neuropeptides and cytokines as well as a range of exogenous molecules (e.g., phenylbiguanide, veratridine, nicotine and capsaicin) [16], [38], [61], [147], [148]. Through their diverse sites of origin, these afferents convey a wide variety of signals to the central nervous system. Only a sub-set of these chemosensitive vagal afferents alter sympathetic vasomotor function. Chemosensitive vagal afferent neurons are quite distinct from the classical chemoreceptors located in the carotid body which respond to arterial hypoxia [161].
Vagal afferent fibers arise from two major locations within the body of an organism: the heart, lungs, bronchi and trachea within the thoracic cavity, many structures of the abdominal viscera [11] and some reproductive organs [39]. Their functional and chemical anatomy has been recently reviewed [11].
In this review, we examine the role(s) of chemosensitive cardiopulmonary and abdominal visceral afferents and their influence on circulatory control mechanisms. We begin by describing the groups of central neurons which contribute to sympathetic vasomotor tone generation and their roles in cardiovascular reflexes. We consider the possibility that activation of chemosensitive vagal afferent pathways leads to differential effects on the circulation mediated by influencing the discharge of premotor sympathoexcitatory (presympathetic) vasomotor neurons of the rostral ventrolateral medulla (RVLM). This hypothesis arose from recent investigations of the effects of cholecystokinin on sympathetic vasomotor outflow to the abdominal viscera [195]. We also review the circulatory effects of activation of chemosensitive vagal cardiopulmonary afferents which mediate the von Bezold–Jarisch reflex and consideration is given to the roles of vagal afferents in the circulatory effects of atrial natriuretic peptide, opioids and cytokines such as interleukin-1β. Although many other agents have been shown to modulate vagal afferent discharge, in this review we have concentrated on those for which effects on the circulation or sympathetic vasomotor function have been described. A brief account of some endogenous substances whose receptors are known to be present on vagal afferent neurons, or which are synthesized by vagal afferent neurons, but which are not known to have effects on sympathetic vasomotor function, is presented in Section 11. A detailed account of the physiology and projections of abdominal visceral and cardiopulmonary vagal afferents is beyond the scope of this review and the interested reader is referred to a number of excellent monographs [6], [11], [58].
Section snippets
Control of sympathetic vasomotor outflow and arterial blood pressure
Neuroanatomical experiments have indicated that five major central nervous system cell groups project to the sympathetic preganglionic neurons in the intermediolateral cell column of the thoracic spinal cord. These include neurons within the RVLM, the caudal medullary midline raphé neurons, the ventromedial medulla, the noradrenergic (A5) neurons of the ventrolateral pons and neurons of the parvocellular region of the hypothalamic paraventricular nucleus [135], [209], [212], [245].
Medullary pathways involved in vagal- and baroreceptor-mediated sympathoinhibition
Sympathoinhibition occurring as a result of activation of arterial baroreceptor afferents is mediated by an intramedullary pathway which involves (i) activation of neurons of the solitary tract nucleus (NTS) via excitatory amino acid receptors, (ii) subsequent excitatory amino acid receptor-dependent activation of inhibitory (GABAergic) neurons of the caudal VLM, and (iii) GABAergic inhibition of RVLM presympathetic vasomotor neurons [36], [79], [80], [109], [231]. A substantial body of
Supramedullary modulation of vagal cardiovascular reflexes
Apart from intramedullary processing of signals arising from activation of abdominal visceral and cardiopulmonary vagal afferents, there is abundant evidence that these signals are relayed to, and modulated by inputs from higher levels of the CNS [183]. Inputs from the insular cortex and medial prefrontal cortex (sometimes referred to as ‘viscerosensory’ and ‘visceromotor’ cortex, respectively [34], [162], [232]), periaqueductal grey and the hypothalamus to the NTS [59], [151], [167], [168] all
Cholecystokinin receptors and vagal afferents
A substantial proportion of the afferent fibers in the vagus arise from a diverse array of structures within the abdominal viscera including the pancreas, liver, stomach and intestines [11]. Some of these are mechanoreceptors located in the smooth muscle of the gastrointestinal tract and are sensitive to intramural tension. Others, found in the mucosal layer of the gut, are sensitive to the products of digestion, exogenous chemicals and neuropeptides such as cholecystokinin (CCK) or its
Vagal afferents and the von Bezold–Jarisch reflex
Vagal afferents arising from the cardiopulmonary region are sensitive to chemicals such as the Veratrum alkaloids (e.g., veratridine), serotonin and phenylbiguanide acting at 5-HT3 receptors [231], ATP [102] and some prostanoids [163], [237]. 5-HT3 receptors are present in high density on vagal afferent neurons in the nodose ganglion [67], [101], [155], [176]. Activation of the reflex results in sympathetic vasomotor inhibition and cardiovagal activation. This phenomenon was first described by
Natriuretic peptides and vagal cardiopulmonary reflex function
Atrial and ventricular stretch results in release of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from cardiac myocytes [53]. Elevated circulating levels of natriuretic peptides have been associated with hypertension, congestive cardiac failure and severe myocardial infarction [190]. Apart from the well-described natriuretic actions of the peptide, ANP inhibits renal and splanchnic sympathetic nerve discharge via activation of vagal C-fibers [201]. A peripheral site of
Cytokines and activation of vagal afferent neurons
Recent investigations of the role of cytokines such as interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) in the febrile, neurohypophyseal and behavioural responses (acute phase response) to simulated infection (endotoxin or lipopolysaccharide; LPS) have highlighted a role for sub-diaphragmatic vagal afferent neurons [61], [75], [222]. Specifically, transection of sub-diaphragmatic vagal afferents reduces symptoms of the acute phase response to LPS or IL-1β [47], [74], [185]. Vagal
Vagal afferents and emesis
Vomiting may be viewed as a physiological defense mechanism against toxins present in foods. Nausea and vomiting are also problematic side-effects of chemotherapeutic agents. The importance of the abdominal vagus was evident when it was demonstrated that electrical stimulation of the abdominal vagus in the ferret results in vomiting accompanied by vasopressin release [7], [85]. However, not all emetic agents act via vagal afferents. Instead, some of these agents act directly on the central
Opioid receptors on vagal afferents and sympathetic vasomotor function
A number of studies have identified opioid receptors on vagal afferent neurons and these undergo axonal transport to their central and peripheral terminations [2], [125], [126], [127]. Opioid receptors are associated with capsaicin-sensitive vagal afferent fibers [124] and so these are unmyelinated vagal C-fibers. Activation of opioid receptors subsequent to right atrial administration of morphine or the methionine–enkephalin analogue, D-ala2-met5-enkephalinamide, produces hypotension and
Neuropeptides and other agents which have receptors on vagal afferents
Endogenous substances have the potential to modulate sympathetic vasomotor function via vagal afferent mechanisms in two major ways. Firstly, receptors for the individual agent may be present on vagal afferent neurons and terminals, a situation described in the preceding sections for CCK, ANP, opioids and the cytokines. Secondly, various neuropeptides are neurotransmitter candidates in vagal afferent neurons and so, via their release in the CNS, may modulate sympathetic vasomotor function.
Other
Conclusions
Chemosensitive vagal afferents convey a broad range of sensory signals to the central nervous system. They monitor gastrointestinal nutrient status, detect circulating peptides released from the atria of the heart, and respond to circulating cytokines during the acute phase reaction to infection [18]. Apart from signalling diverse conditions such as satiety, or infection, it is also apparent that chemosensitive vagal afferents also influence sympathetic vasomotor function. Activation of some of
Acknowledgements
This work was supported by grants from the National Health and Medical Research Council of Australia and Austin Hospital Medical Research Foundation to A.J.M.V.
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