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¹ Department of Physiology, University College London, Royal Free Campus, London, UK

Abstract

Cardiac vagal preganglionic neurones (CVPNs) are located within the dorsal vagal nucleus (DVN) and the nucleus ambiguus (nA). In mammals, CVPNs within the nA have small myelinated axons and mediate major chronotropic effects, those in the DVN have non-myelinated axons and mediate smaller chronotropic, dromotropic and inotropic effects. Numerous studies demonstrate important influences of serotonin (5-HT) at multiple sites controlling autonomic outflows including the nucleus tractus solitarius (NTS) where cardiorespiratory afferent fibres terminate, and the CVPNs and rostral ventrolateral medulla (RVLM), the location of sympathetic premotor neurones. We have demonstrated roles for some of the numerous 5-HT receptor subtypes (5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄ and 5-HT₇) in brainstem regions involved in cardiac control. Intracisternal application of selective ligands was used to study the effect of 5-HT receptors on heart rate and its reflex control. Further electrophysiological studies were also carried out to delineate their location and the mechanisms of action of these ligands. Blocking 5-HT_1A receptors attenuated bradycardias evoked by stimulating baroreceptor and cardiopulmonary afferents but not arterial chemoreceptors, whereas antagonizing 5-HT₇ receptors markedly attenuated all these reflex bradycardias. Within the DVN, nA and NTS, activation of 5-HT_1A receptors could excite or inhibit neurones. In the NTS 5-HT₂ receptors also had variable effects; 5-HT_2B receptors excite and 5-HT_2C receptors inhibit. Antagonism of 5-HT₃ receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT₃ receptors excite DVN and NTS neurones by a glutamate-dependent mechanism. The origin of the glutamate (neuronal or glial) remains unresolved but glia are a possibility as barorecptor-sensitive NTS neurones receive few direct 5-HT-containing synaptic contacts. Thus, 5-HT plays a critical role in the control of vagal outflow to the heart; however, why so many different receptors are involved, and their relative functional roles, remains unresolved.

(Received 18 October 2004; accepted after revision 23 November 2004; first published online 16 December 2004)
Corresponding author D. Jordan: Department of Physiology, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Email: d.jordan{at}rfc.ucl.ac.uk

In both anatomical tracing studies and electro-physiological recordings the cell bodies of cardiac preganglionic vagal neurones (CVPNs) innervating the heart have been localized within the nucleus ambiguus (nA), the dorsal vagal nucleus (DVN) and the region between the two (intermediate group) in a wide variety of species (Nosaka et al. 1979a). In mammals the nA is of relatively greater importance than the DVN though in lower vertebrates this may not be so (Taylor et al. 1999).

The CVPNs found within the two nuclei differ both in their structure and function and this may reflect their phylogenetic origin (Taylor et al. 1999). CVPNs within the DVN have non-myelinated axons (Ford et al. 1990; Jones et al. 1998), and their low rate of ongoing activity shows no obvious relation to respiratory or cardiac variables. They are unaffected by stimulation of arterial baroreceptors but can be activated at short latency by stimulation of non-myelinated cardiopulmonary afferents. In contrast, CVPNs within the nA have small myelinated axons. In anaesthetized animals they have little or no activity but when induced to fire their activity shows a clear increase in relation to the arterial pulse due to a powerful excitatory input from the arterial baroreceptors (McAllen & Spyer, 1978). In addition, their activity is modulated in phase with respiration, being reduced during the inspiratory phase and most active during postinspiration (Gilbey et al. 1984).

On the basis of incremental electrical stimulation of the vagus, it was concluded that cardiac slowing was solely due to myelinated efferent fibres (Middleton et al. 1950). However, when non-myelinated fibres were activated in the absence of myelinated stimulation a slowing of the heart was also observed in a number of species (Nosaka et al. 1979b; Jones et al. 1995). This bradycardia differed from that observed by stimulating myelinated fibres in that it had slower onset and offset and was, at maximum, about 10% of that evoked by stimulating myelinated fibres alone. In addition, stimulating non-myelinated fibres alone has been demonstrated to slow atrioventricular conduction and decrease cardiac contractility (Garcia Perez & Jordan, 2001).

The activation of cardiac vagal outflow by cardiorespiratory afferents involves a multisynaptic pathway within the brainstem. Cardiorespiratory afferents terminate in the dorsal medulla, within the nucleus tractus solitarius (NTS). Within this nucleus, the information is processed and integrated before passing to the output neurones located within the DVN and nA (see Jordan, 2002).

Role of 5-HT in cardiac control

In an early study of the effects of the archetypal 5-HT_1A receptor agonist 8-OH-DPAT on sympathetic activity in anaesthetized cats, Ramage & Fozard (1987) noted that in addition to sympatho-inhibition, intravenous 8-OH-DPAT evoked a vagally mediated fall in heart rate. This effect appeared to be due to an effect on central 5-HT_1A receptors as a similar increase in cardiac vagal drive was observed when 8-OH-DPAT was given intracarebroventricular (Shepheard et al. 1994). The present review concentrates on the role of 5-HT receptors in controlling parasympathetic outflow to the heart since a comprehensive review of their action in controlling sympathetic outflows has already been published (see Ramage, 2001).

A role for central 5-HT-containing pathways in modulating cardiorespiratory reflexes was also suggested in recent experiments on rats depleted of 5-HT by pretreatment with the tryptophan hydroxylase inhibitor parachlorophenylalamine (pCPA). In these anaesthetised animals, heart rate was normal and arterial blood pressure only slightly lower than normal. However, falls in heart rate evoked by stimulating cardiopulmonary afferents, and the sensitivity of the arterial baroreceptor reflex were significantly reduced (Kellett et al. 2005). The NTS, nA and DVN are all innervated by fibres containing 5-HT (Steinbusch, 1981) and, at least within the nA, they make synaptic contact with CVPNs (Izzo et al. 1993). The origin of these fibres is likely to be from within the brainstem. Anatomical studies have described 5-HT-containing neurones within the midline raphe nuclei (pallidus, obscurus and magnus) and others in the ventral medulla, lateral to the pyramids, which innervate VPNs in the nA (Haxhiu et al. 1993). Similar groups of 5-HT neurones also innervate the region of the NTS (Thor & Helke, 1987). In addition, some vagal afferents themselves also contain 5-HT (Nosjean et al. 1990; Sykes et al. 1994) so this may contribute to the innervation of the NTS. In addition to their innervation by 5-HT, these regions also express a wide range of 5-HT receptors. Within the NTS and vagal nuclei binding sites, mRNA and or immunochemical localization has identified 5-HT_1A (Manaker & Verderame, 1990; Thor et al. 1992), 5-HT_2A and 5-HT_2C (Pompeiano et al. 1994), 5-HT₃ (Steward et al. 1993), 5-ht_5A (Oliver et al. 2000) and 5-HT₇ (Gustafson et al. 1996) receptors.

In rabbits, intracisternal application of the 5-HT_1A receptor agonist buspirone potentiated the vagal bradycardia evoked by stimulating upper airway, cardiopulmonary receptors, baroreceptors and chemoreceptor afferents; this potentiation was attenuated by pretreatment with the selective 5-HT_1A receptor antagonist WAY-100635. It is interesting that when given alone, the antagonist attenuated the upper airway, baroreceptor and cardiopulmonary reflex decreases in heart rate but not those evoked by chemoreceptor stimulation (Dando et al. 1998; Skinner et al. 2002). In similar experiments, the 5-HT_1B/1D receptor agonist sumatriptan attenuated upper airway reflex bradycardia and this was blocked by pretreatment with the selective antagonist GR127935 (Dando et al. 1998) (Fig. 1).

View larger version (17K): [in this window] [in a new window]   Figure 1.  Diagrammatic representation of possible sites and receptors within the NTS and vagal motor nuclei at which 5-HT could act to modify heart rate and its reflex control Excitatory receptors are shown in green and inhibitory receptors in red. Neurones within the NTS are differentiated into monosynaptic (receiving afferent inputs), polysynaptic (close to and including the output neurones) and intermediate (those in between). Based on data from Jeggo et al. (2000, 2001), Kellett et al. (2004b, 2005), Llewellyn-Smith et al. (2004), Sévoz-Couche et al. (2000a,b), Wang & Ramage (2001), Wang et al. (1995, 1996, 1997, 1998).

Effects of 5-HT receptor ligands on vagal preganglionic neurones

In anaesthetized, neuromuscularly blocked and ventilated animals recordings have been made from vagal preganglionic neurones and neurones within the NTS. To enable ionophoretic application of ligands to the vicinity of recorded neurones recordings were made either through one barrel of a 5- or 7-barrelled glass microelectrode or through a separate recording electrode attached to the side of the multibarrelled- electrode (Wang et al. 1998; Jones et al. 2002). This latter method allows more control of the tip size and profile of the recording electrode.

Application of 5-HT to dorsal vagal preganglionic neurones (DVPNs) had variable effects, exciting some neurones and inhibiting others (Wang et al. 1995). This should not be surprising because to date 14 different 5-HT receptors have been identified (see Barnes & Sharp, 1999). Clearly the neuronal response will then be dependent on a whole range of factors such as which receptor subtypes are present, their relative numbers, their position in terms of somatic versus dendritic, and the concentration of 5-HT reaching each receptor relative to the receptor affinity. Using more selective agonists and antagonists we demonstrated that activation of 5-HT_1A receptors could either excite or inhibit DVPNs but only the excitations were attenuated by the antagonist pindolol (Wang et al. 1995). Similarly, CVPNs within the nA were excited by application of 8-OH-DPAT and this effect was antagonized by WAY-100635 (Wang & Ramage, 2001). This antagonist also attenuated the excitatory response evoked by cardiopulmonary afferent activation. This excitatory response produced by 8-OH-DPAT is unusual because in other neuronal systems activation of 5-HT_1A receptors usually evokes inhibition. However, as vagal preganglionic neurones are subject to tonic GABAergic inhibitory tone (see Taylor et al. 1999), it is possible that the excitation is mediated by disinhibition rather than a direct excitatory effect (Fig. 1).

Activation of 5-HT₃ receptors, by ionophoretic application of the selective agonist phenylbiguanide (PBG) also activates VPNs and this effect can be attenuated with selective antagonists such as granisetron (Wang et al. 1996). Again, it is unlikely that this excitation is a direct postsynaptic effect on the VPNs themselves. In intracellular recording, in vivo application of DL-homocysteic acid evoked the expected increase in firing associated with a membrane depolarization. However when PBG was applied, membrane potential was little changed but the firing rate increase was associated with increased synaptic noise, suggesting that the major part of the response was due to an action presynaptic to the VPN (Wang et al. 1998). It was subsequently demonstrated that the PBG-evoked excitation was dependent on functioning glutamate receptors as application of DL-2-amino-5-phosphonopentanoic acid (AP-5) and 6-7-Dinitroquinoxaline-2,3-dione (DNQX) at currents selective for blocking NMDA and non-NMDA receptors, respectively, antagonized the PBG response (Wang et al. 1998).

Effect of 5-HT-containing inputs to the NTS

The NTS can be considered the brainstem equivalent of the dorsal horn. Many functionally different afferent inputs terminate here, there are multiple levels of integration and interaction, and descending inputs from other regions of the neuraxis such as the pons, midbrain and hypothalamus can also impose their modulatory effects here (see Jordan, 2002). It has been known for many years that descending 5-HT-containing pathways modify neurotransmission, particularly from pain-related inputs, at the level of the dorsal horn (see Mason, 2001). Similarly, the NTS is known to express a number of 5-HT receptors including 5-HT_1A (Manaker & Verderame, 1990), 5-HT₂ (Pompeiano et al. 1994) and 5-HT₃ (Steward et al. 1993) receptors. Not surprisingly, applying 5-HT to NTS neurones had a variety of effects including excitation, inhibition and biphasic responses and similar variable responses were seen with the 5-HT_1A receptor ligand 8-OH-DPAT and the 5-HT₂ receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-amino propane (DOI), though the effects of selective antagonists on these responses was not tested (Wang et al. 1997). Only activation of 5-HT₃ receptors was relatively consistent with the vast majority of cells showing excitation (Wang et al. 1997; Jeggo et al. 2000) (Table 1). Variable effects of DOI, as seen in vivo, have also been reported by authors performing in vitro studies. Brooks & Albert (1995) reported that activating 5-HT₂ receptors evoked a depolarization and increases in both the amplitude and frequency of synaptic noise but Feldman (1994) could find no evidence for an excitatory effect. More recent in vivo studies to define more clearly the responses to activation of 5-HT₂ receptors have demonstrated several important points and may account for the contradictory in vitro data (Sévoz-Couche et al. 2000a, b). In NTS neurones receiving vagal afferent inputs, using ligands selective for the different 5-HT₂ receptor subtypes, it was observed that activation of 5-HT_2B, and probably 5-HT_2A receptors, had predominantly excitatory effects whist activation of 5-HT_2C receptors predominantly reduced neuronal firing. Moreover, the distribution of effect varied depending on the type of neurone recorded. Based on the variability of the latency of the vagal-evoked response (Doyle & Andresen, 2001; Scheuer et al. 1996) neurones were classified into three groups. Group 1 included those cells likely to be monosynaptically activated whilst group 3 included those polysynaptically activated and group 2 was intermediate between the two. It is interesting that the responses to 5-HT_2C receptors was seen only on group 1 and some group 2 neurones whist those to 5-HT_2B receptor activation were only observed on group 3 and those group 2 neurones unaffected by 5-HT_2C receptors. Clearly, unless selective ligands are used for the different receptor subtypes, and unless some differentiation of the type of cell recorded is made, then inevitably variable data will be produced.

5-HT₇ receptors and cardiovascular control

Most recently, following the cloning of the 5-HT₇ receptor, highly selective antagonists for this receptor have been developed (Hagan et al. 2000; Thomas et al. 2003). This is of interest for several reasons. First, in the hindbrain 5-HT₇ receptor mRNA has only been localized within the NTS (Gustafson et al. 1996). Second, the 5-HT_1A receptor agonist 8-OH-DPAT is now known to also have affinity for 5-HT₇ receptors. Finally, blockade of supraspinal 5-HT₇ receptors has been shown to attenuate the micturition reflex (Read et al. 2003), so the question arose, do 5-HT₇ receptors modulate cardiac vagal outflow?

To answer this question, the effect of intracisternal application of the selective antagonists SB-269970 and SB-656104 on baseline cardiorespiratory variables and cardiorespiratory reflexes was tested. Within 5 min of application, SB-269970 dose-dependently attenuated the fall in heart rate evoked by stimulating cardiopulmonary afferents (Kellett et al. 2005) and the sensitivity of the arterial baroreceptor reflex was also reduced (Kellett et al. 2005). Thus, blockade of either 5-HT_1A receptors or 5-HT₇ receptors can attenuate the reflex decreases in heart rate. However, whereas the chemoreceptor reflex bradycardia was unaffected by blockade of 5-HT_1A receptors, application of SB-229970 significantly reduced this bradycardia also. Where these antagonists are acting to have these effects is, as yet, undetermined. However, as 5-HT₇ receptor mRNA has only been localized within the NTS (Gustafson et al. 1996) this is one possible site. In this respect, preliminary data from our laboratory have demonstrated that topical application of SB-269970 significantly reduced vagus-evoked NTS activity with a time course similar to the reduction in reflex bradycardias (Kellett et al. 2004b). Furthermore, the same dose did not significantly alter ongoing discharge of DVPNs (Fig. 1).

5-HT innervation of NTS neurones

If, as we propose, 5-HT-containing pathways are modifying cardiorespiratory function by an action on 5-HT receptors within the NTS, then NTS neurones involved in these reflexes should be innervated by 5-HT-containing terminals. In a collaborative study we have examined this hypothesis directly in two sets of experiment. Cardiovascular NTS neurones were identified either by their expression of c-Fos following phenylephrine-induced increases in blood pressure (Minson et al. 1997) or by juxtacellular labelling with neurobiotin of single neurones receiving aortic and/or vagal nerve inputs (Jones et al. 2002). 5-HT-containing terminals were identified by immunochemistry using antibodies for 5-HT or the serotonin transporter (SERT). c-Fos-positive cells and single juxtacellular-labelled neurones were surrounded by 5-HT-immunoreactive (IR)- or SERT-IR-positive fibres, although at the light microscopy level it was difficult to determine whether close appositions were indeed synaptic contacts (Llewellyn-Smith et al. 2004). However, when tissue was processed for electron microscopy it was clear that irrespective of whether or not the cell somata were c-Fos-positive or negative, the vast majority (171/173) received no 5-HT-IR-positive terminals and a similar result (114/116) was found for SERT-IR. Of interest, a thin leaflet of glial tissue usually separated 5-HT- or SERT-containing contacts from the NTS cells bodies or dendrites (Llewellyn-Smith et al. 2004). Thus, if 5-HT-containing terminals do directly innervate barosensitive NTS neurones, the innervation is sparse and targeted mainly to more distal dendrites. The question then arises, could glia be involved in neurotransmission within the NTS? (Fig. 1). There are precedents elsewhere within the central nervous system for such a suggestion. It is now well documented that astrocytes express receptors for a number of neurotransmitters, that these receptors can be activated by neurotransmitters released from synaptic terminals and that glial cells can modulate synaptic activity (see Porter & McCarthy, 1997; Araque et al. 2001; Fellin & Carmignoto, 2004).

Conclusions

There is clear evidence that 5-HT-containing pathways within the brainstem can have profound influences on the neurones involved in control of the heart and these are mediated by a variety of different 5-HT receptors that act at different brainstem sites. Whilst the evidence suggests that these pathways are not tonically active at rest in the anaesthetized animal, they are recruited during several different reflexes which modify heart rate. In addition, it is likely that changes in physiological state such as sleep/waking, temperature regulation and alerting/defensive behaviour may recruit these pathways but this requires future investigation.

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Acknowledgements

The work described here was supported by a series of grants from the Wellcome Trust and British Heart Foundation. I would like to thank my numerous collaborators, postdoctoral researchers and PhD students whose hard effort and input made these studies possible. In particular, Andy Ramage, James FX Jones, Yun Wang, Ida Llewellyn-Smith, Matthew Skinner, Ross Jeggo & Dan Kellett have all made important contributions.

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