17.2: Chemical Control of Breathing
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)It perhaps comes as no surprise that the major influence on the reflex drive to breathe comes from the homeostatic need to match ventilation with metabolic demand and maintain blood O2, CO2, and pH within narrow ranges. The chemoreflexes are therefore capable of sensing changes in arterial oxygen, carbon dioxide, and pH, modifying the activity of the brainstem respiratory centers and affecting an appropriate change in alveolar ventilation. These reflexes all act as classical negative feedback circuits and are capable of maintaining despite large changes in O2 consumption and CO2 production by metabolizing tissue.
Before getting into the details of the chemoreceptors, let us take a quick overview of the basic circuitry of the chemoreflexes (figure 17.3). There are two sets of sensors in our circuit: the peripheral chemoreceptors that are in the vasculature, and the central chemoreceptors that are found on the surface of the brainstem. The central chemoreceptors are capable of detecting changes in arterial CO2, while the peripheral chemoreceptors respond to changes in CO2, O2, and arterial pH.
Upon excitation by changes in blood gas values, the receptors fire back to the reflex’s controller, the respiratory centers in the brainstem. This results in an increase in reflex ventilatory drive and a greater motor signal to the respiratory muscles. This produces an increase in alveolar ventilation that corrects the blood gas disturbances and stops the chemoreceptors from firing.
With that basic circuit in mind, let us now look more closely at the chemoreceptors and the ventilatory responses they can induce.
Central Chemoreceptors
We will start with the central chemoreceptors. The central chemoreceptors are comprised of chemosensitive neurons on the ventral surface of the medulla found close to the entry points of the glossopharyngeal and vagus nerves (coincidentally these are the nerves bringing in afferent information from the peripheral chemoreceptors and the pulmonary mechanoreceptors).
Although the central chemoreceptors do not respond to hypoxemia and only respond to rises in arterial CO2, their activity accounts for about 80 percent of the hypercapnic ventilatory response. Given the critical importance of maintaining a normal PaCO2, these are considered the most important chemoreceptors for minute-by-minute regulation of ventilation. Ironically they do not respond to CO2 directly, but rather to changes in pH of the cerebrospinal fluid (CSF).
This complication comes from the fact that the central chemoreceptors are not exposed to the blood, but rather are behind the blood brain barrier and bathed in CSF. Hydrogen ions and bicarbonate cannot pass through the blood brain barrier, but CO2 can. Once through the blood brain barrier, CO2 forms carbonic acid in the reaction that is very familiar to you. It is the hydrogen ion from the dissociated carbonic acid that stimulates the chemoreceptors. So the central chemoreceptors respond to a rise in arterial CO2 via a change in CSF pH. Because there is little protein in the CSF, there is little buffering capability, and pH changes here tend to be greater than in the blood where plasma proteins are plentiful. This makes the central chemoreceptors quite sensitive and partly explains their substantial role in CO2 control.
Prolonged exposure to high CO2, such as in chronic lung disease, can lead to a rise in CSF bicarbonate. This bicarbonate buffers hydrogen ions and reduces the sensitivity of the central chemoreceptors. This partly explains why the hypercapnic ventilatory response diminishes over time in chronic lung patients, such as those with COPD.
Peripheral Chemoreceptors
The peripheral chemoreceptors are directly exposed to arterial blood and are capable of responding to changes in CO2, O2, and pH. There are two populations of chemoreceptive cells in the vasculature (see figure 17.4). One population is found in the aortic arch and is referred to as the aortic bodies. These are wired into the brainstem through afferent fibers that project to and join the vagus nerve. The other chemoreceptor is comprised of the carotid bodies, found in the bifurcation of the common carotid arteries. These connect to the brainstem through the carotid sinus and the glossopharyngeal nerves. The carotid bodies are by far the most important in humans, with the aortic bodies contributing very little to any ventilatory response.
Although the carotid bodies play little role in reflex response to CO2, their response to hypercapnia is more rapid than the central chemoreceptors and so they are capable of breath-by-breath regulation and responding to abrupt changes in arterial PCO2. More importantly the peripheral chemoreceptors are entirely responsible for the response to hypoxia. The mechanism as to how these receptors work is unclear, but cells within the carotid bodies have very high metabolic rates and receive a proportionately high blood flow. It is likely that a decline in oxygen interrupts their metabolism and reduces their inhibitory interaction on neurotransmitter-filled neighboring cells, allowing excitation of the carotid sinus nerve. Their response to a decline in blood oxygen is far from linear. A decline in PO2 below 100 mmHg causes little change in action potential firing, but the rate of firing rapidly increases at PO2s below 50. This is reflected in the hypoxic ventilatory response illustrated in the graph in figure 17.5.
Figure 17.5 shows the hypoxic ventilatory response across a range of alveolar PO2s at normal PCO2. You can see that there is little increase in ventilation until alveolar PO2 is below 55 mmHg, and then ventilation increases very rapidly. This is likely a reflection of the peripheral chemoreceptors, firing rate, which increases rapidly below PO2 of 50 mmHg.
Because of this, the hypoxic ventilatory response normally plays little role in the control of breathing in humans. The hypoxic ventilatory response becomes more significant at altitude when inspired PO2 is low, or more pertinently in lung disease, where alveolar ventilation or gas exchange is compromised.
The hypercapnic ventilatory response (figure 17.6) is much more influential on breathing in humans on a normal day-to-day basis. The response is very linear, with a rise in PCO2 producing a proportionate rise in ventilation, driven of course primarily by the central chemoreceptors, but also contributed to by the afferent activity of the peripheral receptors.
The central and peripheral chemoreceptors keep arterial PCO2 within very fine limits, primarily because of CO2's effect on pH. Alveolar ventilation rapidly increases with even a moderate rise in arterial CO2, but can completely stop (apnea) if arterial CO2 falls below normal (~40 mmHg). The wakeful drive to breathe tends to keep CO2 a little lower than the set-point of the chemoreceptors—a point illustrated during sleep, when the brainstem has complete control of breathing and PaCO2 is seen to rise a few mmHg.
The hypercapnic ventilatory response adapts to chronically elevated arterial CO2, such as in severe lung disease. Here we not only see the CSF increase its buffering capacity with increased bicarbonate, but we also see the chemoreceptors change their set-point. It is not uncommon to see COPD patients with arterial PCO2s above 60.
Hypoxia + Hypercapnia = Potentiation
Finally, the hypoxic and hypercapnic ventilatory responses are not independent, and when they are both present at the same time a potentiation is seen (i.e., the response to hypoxic and hypercapnia is greater than the sum of the two individual responses).
The hypoxic ventilatory response we have just looked at was measured at an alveolar PCO2 of 35.8 mmHg. If the same test is performed at higher PCO2s (figure 17.7), then the hypoxic ventilatory response is much greater, as shown by these upwardly shifted lines when alveolar PCO2 is set to 43.7 mmHg and 48.7 mmHg.
Likewise, the hypercapnic ventilatory response is exaggerated in the presence of hypoxia (see figure 17.8). The hypercapnic ventilatory response we have just looked at was measured at a "normal" alveolar PO2 of 110 mmHg. If the hypercapnic response is measured in the presence of hypoxia, then the curve shifts upward, as shown by the upper lines when alveolar PO2 is reduced to 47 mmHg and 37 mmHg. This potentiation likely comes from the peripheral chemoreceptors, whose firing rate is potentiated in the presence of both stimuli. Consequently, when a patient is both hypoxic and hypercapnic, then they are likely to have a very high drive to breathe, and when this occurs they are likely to feel very short of breath—the topic of the last chapter.
Summary
The chemoreflexes modulate breathing to maintain constant arterial blood gases and pH. These reflexes are initiated by central sensors that respond to hypoxia and peripheral sensors that respond to hypercapnia, hypoxia, and changes in arterial pH. Together these sensors can maintain arterial blood gases within narrow ranges despite large changes in oxygen consumption and CO2 production associated with changes in metabolic rate.
References, Resources, and Further Reading
Text
Levitsky, Michael G. "Chapter 9: Control of Breathing." In Pulmonary Physiology, 9th ed. New York: McGraw Hill Education, 2018.
West, John B. "Chapter 8: Control of Ventilation—How Gas Exchange Is Regulated." In Respiratory Physiology: The Essentials, 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams and Wilkins, 2012.
Widdicombe, John G., and Andrew S. Davis. "Chapter 8" and "Chapter 9." In Respiratory Physiology. Baltimore: University Park Press, 1983.
Figures
Figure 17.1: Brain stem respiratory network. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.1_20220125
Figure 17.2: Lung volume and pulmonary stretch receptor firing. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.2_20220125
Figure 17.3: Chemoreflex circuit. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.3_20220125
Figure 17.4: Peripheral chemoreceptors. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.4_20220125
Figure 17.5: Hypoxic ventilatory response. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.5_20220125
Figure 17.6: Hypercapnic ventilatory response. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.6_20220125
Figure 17.7: Hypoxic ventilatory responses with varying degrees of hypercapnia. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.7_20220125
Figure 17.8: Hypercapnic ventilatory responses with varying degrees of hypoxia. Grey, Kindred. 2022. CC BY 4.0. https://archive.org/details/17.8_20220125