Role of the vasomotor centres

This chapter is vaguely relevant to Section G5(i) of the 2017 CICM Primary Syllabus, which expects the exam candidate to describe the role of the vasomotor centre and the autonomic nervous system in the regulation of cardiac output and venous return". The vasomotor centre is the star of this show, and any discussion of the autonomic nervous system inevitably leads to this central control organ. Fortunately, nobody has ever been asked for an in-depth exploration of this matter in any of the past papers, which means the time-poor exam candidate can easily ignore this section. A detailed understanding of central vasomotor control is not required to write "nucleus tractus solitarius" and "rostral ventrolateral medulla" in exam answers, invoking these names as magical incantations to ward against failure. 

In summary:

Neural Mechanisms of Cardiovascular Integration by Chapleau et al (2004) is probably the definitive peer-reviewed source for this chapter, but considering that it is over 400 pages and the material has zero exam relevance, recommending it to the reader would be preposterous. The next best resource which rolls everything up into a neat peer-reviewed package is Gordan et al (2015), which also happens to be free to read on PubMed. The approach is enviably systematic, and where possible the ensuing summary draws on this structure, keeping the detail while trying to maintain respect for exam relevance. 

But first:

"Vasomotor centre" is not a term we like to use anymore.

Because it is a rather archaic description for a collection of brainstem structures which cooperate and conspire to produce some sort of a net balance between sympathetic and parasympathetic autonomic activity. The term itself originates in the dark age of physiology, when well-heeled gentlemen of independent means dissected animals for fun and made reference to the "bulbar vasomotor centre" to explain the origins of haemodynamic embarrassment which they observed when they crudely probed those animal's brainstem structures. For example, Shore (1891) exposed the floor of the fourth ventricle in rabbits, and poured chloroform directly into the hole. The observed "vasomotor excitation" was attributed to stimulation of central vasomotor structures, though it was short-lived as "one or two drops so applied were sufficient to kill the animal".

The term "vaso-motor" had been used throughout the 19th century to refer to anything vaguely neurological involiving the control of the circulation, but the idea that there was some central regulatory organ was relatively novel. Claude Bernard (1863) demonstrated that high spinal cord lesions produced profound hypotension, which then led Owsjannikow and Dittmar to look for some sort of medullary control centre in the early 1870s. Careful experiments were performed, where minuscule brainstem regions of various experimental mammals were selectively destroyed, until a tiny 3mm area was discovered which was essential for the maintenance of vascular smooth muscle tone. This was the rostral ventrolateral medulla (RVLM). That's not a very memorable name, and "vasomotor" remained in common use, popularised by textbooks such as Julius Althaus' Nervous Diseases: 

"The chief vasomotor centre is situated in the medulla oblongata... Faradisation of this organ causes constriction of all arteries below the seat of irritation, while destruction of it priduces dilatation of the same, likewise below the seat of the lesion".

Animal cruelty notwithstanding, the main objection to the use of this term is that it is inaccurate and vague. Most of the time, when one happens upon an instance of its colloquial use, the user is referring to either the central control of the sympathetic nervous system, or the central autonomic control of the circulation as a whole.  In the event of (god forbid) an exam question or a cross-table viva, it would probably be better to describe the specific structures and to use their real anatomical names. On the other hand, as one can clearly see from what follows, there is a lot about this topic which could be described as "inaccurate and vague", and some might say there is merit in continuing to use a familiar term, as its definition is no less precise than anything else.

Nucleus of the solitary tract

This is a tiny ball of grey matter in the dorsomedial medulla, which receives multiple afferent fibres, most notably from the vagus and glossopharyngeal nerve. In case you ever need to read about it in detail (and in French), Jean (1991) has an excellent review in the Archives Internationales. In short, it is very well connected for its size. Its afferents include cardiovascular baroreceptor input and respiratory input, as well as gustatory and orotactile information. Efferent projections extend to wherever the afferents come from (i.e. what projects to the nucleus tends to receive projections from the nucleus) as well as the cerebral cortex, the spinal cord, the thalami and the hypothalamus. 

For the purpose of this cardiocentric chapter, the main focus should probably be the role of the solitary nucleus in the integration of cardiovascular homeostatic control. To paraphrase Andresen (2004), there are two main roles: one, to mediate a short simple baroreflex loop for vagal rate control, and the other, to regulate the tonic activity of medullary sympathetic pathways. That probably sounds really simple, but in fact looking at diagrams of these pathways recalls Renaissance cartography, swarming with mermaids and kraken, blanks filled with placeholder values like" 3rd order interneuron goes here".

At this stage, usually a textbook would molest its readers' eyes with extensively labelled crosssections of a brainstem as if knowing the precise location of the solitary nucleus will somehow give them an edge in the management of clinical problems involving the baroreflex. This alarming delusion infects much of the neurology and physiology literature. Not to be left behind in the race to be the most confusing and pointless resource on the subject, this author will do the same:

All this really does is impress on the reader that these specks of grey matter have a physiological significance which is vastly out of proportion to their anatomical size, something they probably already knew. For exam purposes, one only needs to know that the NTS receives vagal and glossopharyngeal afferents and projects to numerous locations, most notably the nucleus ambiguus and the sympathetic control organs of the ventrolateral medulla.

Nucleus ambiguus, vagus nerve and cardiac ganglia

An even smaller grey matter focus, the nucleus ambiguus is the site of motor neuron cell bodies which (among other things) innervate the muscles of the pharynx and larynx. Its name apparently means "ambivalent" rather than "vague", as  Jacob Augustus Lockhart Clarke, who described it in 1851, thought that it couldn't seem to decide whether to send its efferents along the vagus or the glossopharyngeal nerve (Haines & Olry, 2010).  The role of the nucleus ambiguus in the regulation of the cardiovascular reflexes is reviewed thoroughly by Wang et al (2006). For the purpose of this discussion, is a body of preganglionic parasympathetic neurons which projects efferent fibres via the vagus nerve to the cardiac ganglion. 

The vagus nerve is the vagus nerve, "quia non determinatur ad aliquam specialem partem, sed per omnia viscera vagatur". For the purpose of cardiac reflex control, the most important fibres are obviously those coursing to the myocardium, via the thoracic cardiac branch. Oblivious to his own earlier objections regarding the frivolousness of arraying anatomical illustrations for the non-surgeon, the author takes this opportunity to reproduce a beautiful image from Cunningham's Text-Book of Anatomy (1914), which is still the best and clearest representation of these structures:

These vagal fibres terminate in the cardiac ganglia, collections of acetylcholinergic neurons which surround the sinoatrial node. In fact they are pretty well distributed in the upper chambers of the heart, around the roots of the venae cava and pulmonary veins, near the AV node, in the interatrial septum, and in the atrial appendages (Baptista & Kirby, 1997). According to most textbooks, there does not seem to be much vagal innervation of the ventricle, though Coote (2013) spends several pages explaining that we might be wrong about this. Anyway: the postganglionic fibres terminate at the pacemaker cells, where the release of acetylcholine activates the I_K-Ach channel, which is a ligand-gated potassium channel. An essentially immediate slowing of the heart rate is thereby produced (Tomson & Arora, 2016), as the flux of potassium out of the membrane hyperpolarises the pacemaker cell and delays the rate of its depolarisation:

So, that is the relatively straightforward efferent parasympathetic signalling pathway for the cardiac reflexes. Any of those that end up slowing the heart rate generally do so through the solitary nucleus / ambiguus / vagus axis. This includes the baroreflex, the Bainbridge reflex, the Barcroft-Edholm reflex, as well as the mechanisms underlying vasovagal syncope. 

Caudal ventrolateral medulla

This structure could easily be grouped with the nucleus ambiguus as a part of the overall parasympathetic efferent process. This little pile of drowsy GABA-secreting interneurons acts as the brakes for the sympathetic nervous system, inhibiting the tonic activity of the sympathetic regulatory centre and therefore acting in synergy with the rest of the vagal efferents. The importance of its role is revealed by the catastrophe in its absence. When Cravo & Morrison (1993) damaged the CVLM regions of rats, their MAP went from 80 to 130mmHg and their splanchnic circulation vasoconstricted by 200%, mainly under the normal tonic output of the sympathetic centre. In short, this vasomotor nucleus maintains some sort of calm restraint in the sympathetic output of the medulla, and acts in coordination with the vagal centres to mediate vasodilation at the same time as the vagus mediates bradycardia, thus decreasing the blood pressure.

Rostral ventrolateral medulla and sympathetic efferents

This, for lack of a better word, is the vasomotor centre. It is thought that clonidine exerts its antihypertensive effect by binding to α2 receptors in this exact region (Ernsberger et al, 1990). It contains presympathetic (mainly glutamate-secreting) C1 neurons which project to the spinal cord and which maintain a constant tonic firing rate. In fact to say that this region "projects to the spinal cord" is unfairly vasocentric as it conceals from the reader the true extent of the connections here, and they really stretch in all directions, to multiple central nervous system targets. But yes, in the spinal cord the targets of descending projections from the RVLM are preganglionic neurons of the sympathetic nervous system, sitting in the thoracic intermediolateral column. 

An extensive discussion, more than is required for any normal person, is offered by Guyenet & Stornetta (2004). Without tediously re-grinding all the minor details, it will suffice to say that the constant tonic activity of this brainstem region is responsible for most of the sympathetic contribution to peripheral vascular resistance (the rest being contributed by whatever circulating catecholamines are floating around). At the same time, sympathetic innervation of the heart also exerts a counter-regulatory effect (opposing vagal stimulus), increasing heart rate and contractility. Apart for the inhibitory effects of descending control (eg. the GABA neurons in the caudal ventrolateral medulla), this centre is also affected by numerous circulating mediators, for example, angiotensin. 

 It will suffice to say that, unlike the rapid effects of vagal acetylcholinergic transmission, sympathetic effects take slightly longer, because they are mediated by a secondary messenger (cAMP) which in turn activates cyclic nucleotide-gated ion channels. Because the synthesis and degradation of cAMP add extra steps into the process of signal transduction, the sympathetic effect is slower. The cardiac effects of the sympathetic nervous system are mainly mediated by β1-receptors, and the vascular effects are mediated by α1 receptors. The vascular effectors are the smooth muscle fibres of the small arterioles: noradrenaline release here tends to produce a calcium-mediated contraction. In case anybody needs a detailed reference, Bruno et al (2012) have produced an excellent in-depth review of these vascular regulatory functions. Anyway, the sympathetic nervous system is a large enough topic that the college had allocated whole swaths of their syllabus document to it, and to revisit this here would represent a descent into silliness.