Function of baroreceptors and clinical relevance of the baroreflex

This chapter is probably relevant to Section G5(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the function of baroreceptors and ...relate this knowledge to common clinical situations". This is a separate syllabus item, distinct from Section G3(vi),"describe the cardiac reflexes".  It was also the subject of Question 16 from the second paper of 2014 and Question 8 from the second paper of 2007, which asked the trainees to explain or describe the role of the baroreceptors in the control of blood pressure.  Thus, the baroreflex got its own dedicated page. All the other less popular cardiovascular reflexes, as well as the cellular mechanics involved in the stretch-sensitive mechanoreceptors, are banished to the generic "cardiac reflexes" chapter. 

In summary:

Neurology of the baroreceptor reflex arc

In most diascussions of cardiac reflexes, the baroreflex is usually discussed first, not only because it is more "important" (some might say everything is important) but also because it is probably the best known reflex, and it has been known for the longest time.  This also means the author can indulge his fascination with old-school physiology papers.  Spyer (1981), though it was published forty years ago, is still the most useful comprehensive overview of this topic (102 pages!). A couple of extra decades here or there are not particularly important, as the neural pathways for this reflex were first discovered in 1852 (Estañol et al, 2011) and the behaviour of the reflex was fully described by the 1970s (looking at review articles like Kirchheim, 1976). If we had to force this concept into some brutally stupid exam-focused matrix, it would look like this: 

• Stimulus:  Pressure (stretch)
• Sensors: Stretch-sensitive mechanoreceptors in the carotid sinus and aortic arch
• Afferent nerves:
  • Vagus carries afferent fibres from the aortic arch
  • Glossopharyngeal nerve carries fibres from the carotid sinus
• Processor: Nucleus of the solitary tract and the caudal ventral medulla
• Efferent nerves: 
  • Sympathetic fibres to the heart and peripheral resistance vessels
  • Vagal efferents to the cardiac ganglion (heart rate)
• Effector:  Myocardium, SA and AV nodes, vascular smooth muscle

A crude schematic is probably in order, particularly if it is an excuse to draw squidlike neurons and flaunt some beautiful anatomical art by Joseph Maclise (1841).

There is probably some merit in walking through this in some detail. This reflex arc is a fairly fundamental property of the human cardiovascular system, and one might be forgiven for dwelling on it for a minute. According to Spyer (1981), much of what we know about it seems to have come from animal experiments, and the favoured method of tracking the neural pathways has generally been to sever the nerve proximally, demonstrate the abolition of the reflex, and then to track the degeneration of the axons to see where the fibres lead. 

Carotid sinus mechanoreceptors

The carotid sinus, anatomically, is a small neurovascular structure located at the dilated portion of the common carotid artery (the "carotid bulb"), just at the point of its bifurcation. It is not to be confused with the carotid body, which is a PaO₂ / PaCO₂ sensing chemoreceptor at the same location. For lack of a dirty limerick, to help their memory trainees may recall the alliteration that sinus senses stretch, and body senses breathing. The sinus itself is just a bundle of nerve endings which is located in an area of thickened adventitia around the carotid bulb. This image from Porzionato et al (2019) was disgracefully vandalised to demonstrate the thinning of the (pink) arterial media and the thickening of the (purple) adventitia, all the better to bring the nerve endings closer to the arterial lumen (as the nerve endings are mainly seen at the medio-adventitial junction). The silver-stained nerve endings are dark brown.

So. The carotid sinus receptors sit in the adventitia on the outer edge of the dilated common carotid, whereas the carotid body (glomus) is the pea-shaped structure nestled into the bifurcation of the vessels. The exact area covered by these mechanoreceptors is probably quite variable, as is the actual location of the dilatation (West et al, 2018). Generally, it is assumed that the entire surface of the dilatation is well-innervated, i.e. that whole 2-3cm segment of artery is the mechanoreceptor complex, rather than any specific discrete patch. That probably has clinical significance; when you massage the carotid sinus, your fingers do not need surgical precision.

Aortic arch mechanoreceptors 

Now that we have already discussed the mechanism of signal transduction in stretch-sensitive mechanoreceptors, to reveal other mechanoreceptor areas should be straightforward from a narrative perspective. What if baroreceptors, except aortic? From a purely mechanical point of view, these sensors are exactly the same as the ones in the carotid bulb. In fact, as they are closer to the heart, one might expect them to be more important in the regulation of blood pressure.

From an ultrastructural point of view, these receptors seem to obey the same rules as the carotid receptors: they sit in at the medio-adventitial junction.  Their distribution seems to be somewhat variable. The most commonly studied subjects for aortic baroreceptor experiments have been rats, mice, rabbits and cats, who all have slightly different areas of distribution. Human data seems difficult to track down. If we extrapolate from animal studies (Aumonier, 1972), we would expect the aortic baroreceptors to be found in the area of the aortic arch, mainly confined to a "saddle-shaped" area between the brachiocephalic trunk and the origin of the left subclavian.  This patch of sensors is not a circumferential area, i.e. it only wraps around about half of the aortic arch. The aorta is also not the only site for such mechanoreceptors: Aumonier found receptor tissue in various patches, all the way up and down the proximal greater vessels, including along the carotid and subclavian arteries:

The observant reader will hasten to point out that this is clearly the aortic arch of some nonhuman mammal, and that this distribution may be completely different in people. To maintain their sanity, these readers should be reminded that interspecies and intraspecies variation of greater vessel plumbing is so varied that nobody should ever expect to confidently know the One and Only Baroreceptor Arrangement. There probably isn't one, and from a sensor efficacy perspective, who cares where the trick of chance has thrown them - as long as they are measuring the distension of a large proximal artery.

Afferent fibres from carotid and aortic baroreceptors

From the mechanoreceptors, both myelinated (A) and unmyelinated (C) afferent fibres travel up to the central nervous system. The large myelinated A-fibres carry fast signals which mediate second-by-second adjustments, and the slower C fibres presumably maintain some sort of slower baseline level of regulation (Porzionato, 2019).  There are two main afferent nerves here: the carotid sinus nerve and the aortic branch of the vagus nerve. 

The carotid sinus nerve, as the name suggests, innervates the carotid sinus barosensors. It courses anteromedially to the internal carotid artery and joins the body of the glossopharyngeal nerve at the base of the skull, where its cell bodies lie in the petrosal ganglion.

The aortic branch of the vagus, otherwise known as the "aortic depressor nerve", innervates the aortic bodies and baroreceptors. It is a branch of the vagus or superior laryngeal nerve, and its cell bodies reside in the petrosal ganglion.

The nodose and petrosal ganglia lie in the jugular foramen, and represent the last stop before the nerve fibres enter the brainstem. There, the afferent nerves synapse with neurons in the nucleus of the solitary tract. Both types of afferents mainly use glutamate as the neurotransmitter, i.e. the activation of baroreceptor afferents is an excitatory stimulus for this nucleus.

The nucleus of the solitary tract (NTS)  is a tiny group of mostly sensory interneurons in the posterior medulla, which is involved in regulating the autonomic nervous system. Its other roles include receiving information from the middle ear (via the tympanic branch of the glossopharyngeal nerve), receiving taste information via the chorda tympani branch of the facial nerve, and mediating the cough and gag reflexes. For this barocentric discussion, we will focus on its role in the negative feedback loops which control blood pressure and heart rate. The nucleus of the solitary tract puts the "negative"  into "negative feedback" by receiving the excitatory stimulus from the afferents, and translating this into an inhibitory (GABA-mediated) stimulus. In response to the glutamate-mediated excitation of the NTS by baroreflex activation, GABA-secreting neurons from the caudal ventrolateral medulla spray nice calming GABA all over the sympathetic regulatory centres in the rostral ventrolateral medulla. 

The rostral ventrolateral medulla (RLVM) is the "vasomotor" centre, discussed in great detail by Brown & Guyenet (1985). It is a regulatory lever, pulled in one direction by excitatory glutamate-mediated neurotransmission, and in the other by GABA-mediated inhibitory signals. Under resting conditions, this nucleus has a constant tonic output, which is modulated by the abovementioned signals. Thus, the excitation of barosensors ultimately leads to an increase in GABA input, which has a depressant effect on the firing rate of RLVM neurons.

Efferent sympathetic fibres regulate blood pressure.

The rostral ventrolateral medulla communicates with (cholinergic) preganglionic neurons in the spinal cord. These, in turn, communicate with noradrenergic neurons in the sympathetic ganglia  The output of the rostral ventrolateral medulla is distributed widely into the sympathetic nervous system, and has numerous effects, of which the most important is the α-1 mediated tonic control of peripheral vascular resistance. For example, when blood pressure drops and baroreceptor firing rate decreases, the sympathetic efferent part of this reflex produces arteriolar vasoconstriction, particularly in skeletal muscle. Additionally, sympathetic fibres through the stellate and middle cervical ganglia innervate the conduction system of the heart, providing β-1 mediated control of heart rate.

 Efferent fibres via the vagus nerve regulate the heart rate.

The nucleus of the solitary tract depresses heart rate by activating vagal efferents, which communicate with the cardiac ganglion. Increased cholinergic transmission along this efferent pathway inhibits the automaticity of the sinoatrial node, and influences the rate of transmission through the AV node. The right vagus does the SA node and the left vagus does the AV node, with enough overlap that the loss of a vagus does not produce total parasympathetic denervation. That means that the right vagus is more important, as the SA node dictates the heart rate, and the AV nodal conduction delay is a minor player (Parker et al, 1984). Generally, vagal input into the nodes is described as being more important than sympathetic input.

Baroreflex regulation of heart rate and cardiac output

In summary, and walking through this process in baby steps, this is what happens when the baroreflex is triggered by an abrupt drop in blood pressure: 

• Decreased blood pressure (eg. upon standing upright from a prostrate position, or the sudden loss of blood volume) results in a decreased baroreceptor firing rate
• Decreased baroreceptor firing rate decreases the secretion of GABA from the caudal ventrolateral medulla
• This decreases the inhibition of tonic sympathetic output by the rostral ventrolateral medulla.
• Thus, sympathetic nervous activity is increased, which results in α-1 mediated peripheral vasoconstriction, including skeletal muscle and the splanchnic circulation
• At the same time, vagal efferent input into the SA node decreases, which increases the automaticity of the SA node, this increasing the heart rate.
• Increased heart rate increases cardiac output; with increased peripheral vascular resistance, this translates into an increase in blood pressure.

Because of the presence of fast myelinated fibres in the afferent and efferent arms of the reflex, control of vascular tone and cardiac output can be very rapid. Borst & Karemaker (1983) were able to time the vasonconstrictor response very precisely in patients whose carotid sinus nerve was already instrumented with a stimulator. As you can see, the response was almost immediate:

To be precise, the investigators recorded a latency of about 0.5-0.6 seconds for a change in sinoatrial node rate (the P-P interval), about 1.0 second latency for a prolongation of the PR interval (reflective of increased AV nodal conduction delay), and about 2-3 second latency for the vasodilator response. The rapid vagal effect is said to be related to the direct activity of acetylcholine on special inward-rectifying potassium channels; whereas other effects (eg. noradrenergic vasoconstriction) rely on the comparatively slower cAMP second messenger system.

Threshold for baroreceptor stimulation

How sensitive is this reflex? Turns out, parts of it are very sensitive indeed. Donald & Edis (1971) isolated carotid sinuses and aortic arches of dogs to see what the application of pressure to these structures will do to the systemic blood pressure. As the pressure to the barosensors was increased, so systemic blood pressure decreased, and the authors were able to plot these on a graph of pressure vs. pressure:

As you can see, the aortic arch is not equal to the carotid sinus, where it comes to sensitivity and responsiveness. The threshold pressure for the aortic arch baroreceptor reflex was about 110 mm Hg compared with about 50 mm Hg for the carotid sinus, which suggests that the aortic reflex manages the blood pressure peaks, and the carotid sinus takes care of the troughs. The exact values reported by different authors for these values will be different across sources because humans are beautiful unique snowflakes and each one will have their own individual baroreceptor sensitivity profile; for example Suarez-Roca et al (2021) give 60 mmHg as the threshold for carotid  baroreceptor activation, and Sundlöf & Wallin (1978) argue that it changes over the course of normal ageing (45mm in your thirties, 80 mmHg in your sixties).

The activity of these receptors is constant and tonic, obsessively micromanaging the degree of peripheral arteriolar vasoconstriction. There is an immediate proportional response to even the transient fluctuations related to respiration. Here one can see a recording made by Sundlöf & Wallin (1978) from the peroneal sympathetic efferents of healthy volunteers, showing spikes of sympathetic activity following every breath-related dip:

The specific firing rate response of the caroid and aortic baroreceptors has several nonlinear and time-dependent features, well summarised by the excellent baroreflex chapter from Ottensen's  Applied mathematical models in human physiology (2004). To borrow their summary:

• Threshold: the minimum value for blood pressure change at which the baroreceptors will react with a change in their firing rate, which is different depending on many factors, for example it is higher in the normal range of pressures, and depending on how abrupt the change is (slow changes need to be of a greater magnitude to trigger a response). There are numerous influences on this sensitivity threshold, well explored in Chapleau et al (2006) 
• Assymmetry: the firing rate has a hysteresis, i.e. it increases exponentially with increasing carotid sinus pressure, but also plateaus at very high pressures. the steepest part of the response seems to be around the normal systolic pressure range, i.e. 100-140 mmHg.
• Step response: a step change in the carotid sinus pressure results in a step change in the firing rate followed by a resetting phenomenon
• Adaptation or "resetting": sustained changes in blood pressure result in the baroreceptor firing rate returning to baseline values.