The function of the carotid bodies is related to their unusual structure. They have an extremely high metabolic rate (about three times that of the brain) but their rate of perfusion by blood from the carotid arteries is even higher: 10 times that which would be expected. This blood flows through capillaries (Fig. 9.2A and B) which surround the sensory elements (the glomus or type I cells) that monitor blood Po₂. The type I cells seem to be supported by type II (sustentacular) cells, whose function is still not clear. The type I cells send their information to the brain via the carotid sinus nerve, a branch of the glossopharyngeal nerve (Fig. 9.2A and B), which also provides them with sympathetic and parasympathetic innervation. A separate supply of sympathetic fibres from the nearby superior cervical ganglion innervates the carotid bodies’ blood vessels.

The overall effect of this extensive sympathetic and parasympathetic supply to the carotid bodies is that their sensitivity can be altered by:

As far as these influences on neurotransmission from the chemoreceptor cells to the afferent sensory nerve endings is concerned it has become frustratingly obvious that, like many CNS synapses, there is a complex interplay of neuromodulators. However, the general consensus is that whereas sympathetic activity may mildly modulate carotid body function it does not have powerful effects on hypoxic ventilation. Dopamine, on the other hand, appears to be an important neuromodulator in the carotid body, inhibiting ventilatory responses to hypoxia.

The embryological origin of the carotid bodies provokes an interesting speculation. As a mammalian embryo develops its structure changes, resembling successive adult forms of more primitive species, starting with the most primitive and finally reaching mammalian form. This is the (now questionable) concept that ‘ontogony recapitulates phylogeny’. During our fish-like phase in the womb those structures that are going to become our O₂-sensitive carotid bodies are represented by the gill arches of the fish-like embryo. It is the gills of fish that are their sensors of O₂ lack. It is therefore postulated that our carotid bodies are a residue of the mechanism by which our fishy ancestors detected O₂ lack in their watery environment.

Activity in the carotid bodies is measured experimentally as the frequency of discharge of action potentials in the carotid sinus nerve. Increased activity expresses itself in the whole animal as an increase in ventilation. Hypoxia stimulates peripheral chemoreceptors, which is unusual, as the activity of almost all other organs is depressed by it.

During eupnea under normoxic conditions most of the drive to breathe comes from central chemoreceptors, and also neural mechanisms associated with wakefulness. Evidence that the peripheral chemoreceptors provide some drive to breathe comes from the observation that in patients who have been subjected to carotid body denervation arterial Pco₂ is elevated by up to 0.8 kPa.

The effect of decreasing a subject’s arterial Po₂ by giving them increasingly hypoxic gas to breathe is shown in Figure 9.3.

It can be seen that Pao₂ must be reduced considerably (to about half normal) before breathing is stimulated, and that very low partial pressures of O₂ depress breathing.

Increased levels of arterial CO₂ (hypercapnia) also stimulate peripheral chemoreceptor activity, probably by increasing [H⁺] within the glomus cells, in the same way as increased extracellular acidity increases chemoreceptor activity and breathing.

What is the actual physiological stimulus to the carotid bodies? It is difficult to see how the absence of something, in this case O₂, can be a stimulus. A number of different observations combine to give us a clue:

These observations explain the two clinical conditions that result in vigorous activation of peripheral chemoreceptors: hypoventilation and hypotension due to haemorrhage. Under these conditions there is a build-up of metabolites resulting from the supply of O₂ to the chemoreceptors being insufficient for their high metabolic needs, owing to the inadequate oxygen content of the blood or inadequate blood flow to carry O₂ to the chemoreceptors and wash metabolites away.

In summary, peripheral chemoreceptors are stimulated by lack of O₂, excess of CO₂ and excess of [H⁺]. These factors cause a build-up of metabolites, which are the specific stimulus to these receptors. Lack of O₂ is a stimulus unique to peripheral chemoreceptors, but O₂ lack must be pretty severe to produce an effect on breathing. Why is there such a modest response to the lack of such an important requirement of the body?

The answer to the above question is that it would be a waste of time having a more sensitive detector of O₂ lack because the shape of the oxyhaemoglobin dissociation curve would defeat its sensitivity. You can see from the oxyhaemoglobin dissociation curve shown in Figure 8.2 (p. 103) that even if Po₂ is reduced to 8 kPa, haemoglobin is still 90% saturated. Also, Po₂ can rise to infinity and haemoglobin can only be 100% saturated. This useful situation means that ventilation of the lungs can halve or double without the amount of O₂ being carried changing very much. But by the same token, a mechanism that relied on O₂ saturation to control breathing under normal circumstances would lack sensitivity, because saturation does not change much over a large range of partial pressure.

The importance of the peripheral chemoreceptors lies in the fact that they are the only mechanism in the body by which low O₂ tension can stimulate breathing, and when tension falls sufficiently this stimulation is very vigorous.

Hypoxic stimulation of breathing is also opposed by changes in CO₂ and [H⁺], because as breathing begins to be stimulated CO₂ is washed out of the blood, arterial H⁺ falls and the drive to breathe from these two sources is reduced, producing what is sometimes called the hypocapnic brake (Fig. 9.4). Just how powerful a drive to breathe hypoxia can be is demonstrated if this braking effect is prevented by adding CO₂ to the inspired air to keep its levels constant in the blood. Under these circumstances hypoxia produces 10 times the effect produced if CO₂ is allowed to be washed out.

Peripheral chemoreceptor activity primarily increases breathing; however, it has minor effects in constricting peripheral blood vessels (except those of the skin), reflexly increasing heart rate and stimulating secretion of the adrenal glands. These three effects combine to increase arterial blood pressure.

The response of the body to sustained hypoxia, of the kind one encounters at altitude or when the lungs are so damaged by disease that they cannot efficiently transfer O₂ to the blood, differs from the acute response described above.

For example, in adult human subjects hypoxia lasting for about an hour produces an immediate increase in ventilation (in 3–5 minutes) followed by a decrease to a steady state level higher than the control, normoxic level. This occurs even when Paco₂ is kept constant and this phenomenon is called hypoxic ventilatory decline. This may be due to hypoxic CNS depression. On a longer time scale, in animals at least, there is a ventilatory acclimatization characterized by a time dependent increase in ventilation which stabilizes at a value greater than the response to acute hypoxia (Fig. 9.5). This response is somewhat confusingly called acclimatization to short-term hypoxia (ASTH) if only to distinguish it from acclimatization to long-term hypoxia (ALTH) which involves the situation found in natives or very long-term residents at altitude. The major mechanism of ASTH appears to be an increased sensitivity of the carotid body to hypoxia (Fig. 9.5) and not, as was once thought, changes in the CSF surrounding the central chemoreceptors.

However, in the longer lasting clinical condition, or at altitude, arterial Po₂ is reduced, causing stimulation of the peripheral chemoreceptors, which in turn increases ventilation. In the high-altitude situation this hyperventilation washes out CO₂ from the blood and cerebrospinal fluid and they become more alkaline, reducing the drive to breathe (mainly at the central chemoreceptors) below the increased level that is appropriate for the reduced atmospheric Po₂. After a day or two the active transport system of the blood–brain barrier returns the [H⁺] of the CSF to normal. This restored drive from CO₂ and the extra drive from O₂ lack goes part-way to achieving the required ventilation. Within a few weeks at altitude the kidneys excrete extra and restore blood [H⁺] which, together with the hypoxic drive to the peripheral chemoreceptors, stimulates breathing to an appropriate level.

Some unfortunate patients with respiratory disease do not make this compensation, particularly if they are of the type picturesquely described as a ‘blue bloater’. This piscine description relates to patients with chronic obstructive pulmonary disease who have marked arterial hypoxaemia and CO₂ retention but do not seem to be breathless. They are blue because they are cyanosed and bloated by congestive heart failure. These patients have adapted to high arterial Pco₂, and so the majority of their drive to breathe comes from O₂ lack detected by the peripheral chemoreceptors. These individuals are particularly at risk if they require a general anaesthetic (see below).

Anaesthetists measure anaesthetic effect in terms of MAC (minimal alveolar concentration for anaesthesia). The peripheral chemoreceptors are extremely sensitive to inhalation anaesthetics (Fig. 9.6). The consequences of this for patients with lung disease receiving anaesthesia are important. They cannot respond when challenged by hypoxia and, if of the ‘blue bloater’ type, who has already lost his drive to breathe from CO₂, will stop breathing when anaesthesia abolishes his drive from hypoxia. You can see from Figure 9.6 that quite low levels of anaesthesia, of the order of those found in the postoperative period, when the patient appears able to look after himself, can seriously blunt the response to hypoxia.

Unlike the peripheral chemoreceptors the central chemoreceptors are not stimulated by hypoxia. In fact, severe hypoxia depresses breathing in adults by a direct action on the respiratory complex in the brainstem.

Furthermore, the peripheral chemoreceptors respond to changes in Pco₂ within seconds, whereas the response of central chemoreceptors takes about 5 minutes to reach equilibrium. This delay is thought to contribute to the instability of breathing in patients with Cheyne–Stokes respiration, where breathing waxes and wanes for no apparent reason.

Although slower to respond than the peripheral receptors, central chemoreceptors are responsible for about 80% of our sensitivity to CO₂. The difference in speed of response can be understood as the central receptors are situated in the brain, behind what is known as the ‘blood–brain barrier’.

Although no discrete structures such as the carotid bodies have been identified as central chemoreceptors, perfusing the ventrolateral surfaces of the medulla with acidic solutions or solutions with a high Pco₂ stimulates breathing. Intracellular recordings in the neurons 500 μm or so below the surface of the brain in the regions shown in Figure 9.8 reveal that the frequency of discharge of these cells increases as the acidity or Pco₂ of the interstitial fluid surrounding them increases. This leads to the question, is it CO₂ or H⁺ produced by the acidifying effects of CO₂ that is the stimulus? A great deal of careful research indicates that the specific stimulus to the central chemoreceptor neurons is intracellular [H⁺], which is determined primarily by the Pco₂ of the cerebrospinal fluid.

As well as being acidic, CO₂ is a highly diffusible gas which is important in the relationship between arterial blood and cerebrospinal fluid (CSF) which is established across the blood–brain barrier. The activity of the blood–brain barrier makes the CSF bathing the brain and spinal cord the most closely controlled environment in the body. Lipid-soluble molecules such as O₂ and CO₂ diffuse freely between blood plasma and brain. Ions such as H⁺ and move under strict control, and are often pumped against their concentration gradients by active transport when it is necessary to control the environment of the brain. The capillaries whose walls form the blood–brain barrier are specialized to produce the CSF from plasma in a region known as the choroid plexus (Fig. 9.8B).

Carbon dioxide acidifies the intracellular environment of the central chemoreceptors by displacing the reaction

to the right, producing H⁺, which is probably the specific stimulus of the central chemoreceptors. It is difficult to see at first glance why the above reaction, which produces both acid H⁺ and base (), acidifies a solution (but remember, it is the ratio of H⁺/ that determines acidity, and there is a lower concentration of H⁺ than in plasma; therefore, the addition of one of each of the ions has a bigger effect on H⁺ (see p. 117). Because H⁺ passes through the blood-brain barrier with difficulty, increases in arterial H⁺ do not affect the central chemoreceptors if arterial Pco₂ is kept constant.

The ion-pumping activity of the blood–brain barrier is particularly important in compensating for chronic disturbances of the composition of the CSF, such as occur during long stays at altitude or in chronic lung disease. Small and acute decreases in blood CO₂, caused by singing, for example, do not depress breathing because of the horizontal part of the Pco₂/_E curve (Fig. 9.7). On average, increasing people’s Pco₂ by 0.3 kPa doubles their minute ventilation.

It is very rare for either arterial Po₂, Pco₂ or H⁺ of a healthy individual to change without changes in the other two (unless you fall into the hands of a respiratory physiologist). The stimulus to breathe that builds up when you hold your breath or rebreathe from a plastic bag involves changes in all three of these variables.

The overall effect of changes in all three was described by a formula devised by Gray in 1945:

where VR is the ratio of ventilation during asphyxia to unstimulated ventilation. This formula is more important as an illustration that no single factor controls ventilation than as a quantitative estimate.

The way in which hypoxia and hypercapnia combine to stimulate breathing is shown in Figure 9.7, where each curve represents a Pco₂/_E relationship at a different Po₂. With progressive hypoxia the curves are seen to steepen, producing a greater ventilatory response than would be produced by the simple sum of the two stimuli. On the other hand, it is not unusual for the arterial Po₂, Pco₂ or [H⁺] of patients to be changed independently by their disease. Most usually this change consists of a fall in Po₂ while Pco₂ is maintained close to normal.

Chemical control of breathing determines minute ventilation, with changes taking place over a matter of one or more minutes. The pattern of breathing that makes up this minute ventilation is determined by the neural control of ventilation, which can bring about changes in pattern in fractions of a second. This process is dealt with in Chapter 10.

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