Chemical control of breathing

Book pp. 937–942 · asked 5 times in NTRUHS papers

In one breath

Breathing speeds up when PCO₂ or H⁺ rises and when PO₂ falls, and the extra ventilation then pulls the blood back toward normal. Peripheral chemoreceptors in the carotid and aortic bodies chiefly sense a low PaO₂, while central chemoreceptors under the medulla sense the H⁺ that CO₂ makes in brain fluid. CO₂, acting mostly through the central receptors, is the everyday driver; hypoxia drives breathing hard only once PO₂ falls below about 60 mmHg.

Builds on: Respiratory centers (neural control) · Carbon dioxide transport · Oxygen–hemoglobin dissociation curve · Leads to: Acclimatization to high altitude · Hypoxia · Oxygen therapy · Asphyxia, hypercapnia and hypocapnia

The three chemical stimuli

• The H⁺, PCO₂ and PO₂ of arterial blood strongly shape breathing. Ventilation rises with PCO₂ and H⁺ and changes inversely with PaO₂.
• Hypoxia, hypercapnia and acidosis all stimulate breathing. The extra ventilation raises PO₂, lowers PCO₂ and raises pH, so the loop corrects itself.
• Two sets of receptors detect the changes: peripheral and central chemoreceptors.

Stimulus	Main sensor
Low PaO₂	peripheral chemoreceptors
High PaCO₂	central (peripheral add up to 40%)
High H⁺	central, through brain H⁺

Blood H⁺ gets into the brain only slowly, so a fall in blood pH on its own acts first through the peripheral receptors (see metabolic acidosis below).

Peripheral chemoreceptors

• They lie in the carotid bodies and aortic bodies.
• They sense the PO₂, PCO₂ and pH of arterial blood, but are most sensitive to a fall in PaO₂.
• They signal the DRG in the medulla, which steps up ventilation.

Don't copy your book's one-line summary

The chapter summary says the peripheral chemoreceptors are more sensitive to PCO₂ than to PO₂. The chapter’s own text says the opposite, and the text is right: these receptors respond chiefly to hypoxia, while CO₂ works mainly through the central receptors.

Carotid bodies

• Corneille Heymans first showed that they work as chemoreceptors, and won the Nobel Prize in 1938.
• Site: on both sides, where the common carotid artery forks into internal and external carotids, near the base of the skull. The carotid sinus is a separate structure: the widened first part of the internal carotid, which houses baroreceptors.
• Nerve: afferents run to the brainstem in the glossopharyngeal nerve, through its carotid sinus branch.

Feature	Value
Width	about 2 mm
Weight	about 2 mg
Blood flow	about 2 L/100 g/min
Flow compared with brain	about 40 times; highest in the body
Metabolic rate	about 3 times brain

• Why the huge flow matters:
  • small changes in blood PO₂, PCO₂ and pH are picked up easily;
  • the carotid body burns a lot of O₂, yet its own PO₂, PCO₂ and pH stay virtually equal to arterial blood. So it reads the arterial values, not its own.
• Its cells sit among fenestrated sinusoidal capillaries.

Type I and type II cells

Type I (glomus) cells are the sensors.

• Round, about 10 µm across, neuroectodermal in origin; they resemble adrenal chromaffin cells and peripheral neurons.
• Their membranes carry voltage-gated ion channels. Their granules hold norepinephrine, dopamine, substance P, met-enkephalin and acetylcholine.
• In hypoxia they release these, mainly dopamine, which acts on D2 receptors on the glossopharyngeal endings and fires the carotid sinus nerve.
• Fenestrated capillaries press close against them, so they sample the arterial gases easily.

Type II (sustentacular) cells wrap around clusters of glomus cells and support them, much as glia support neurons.

Aortic bodies

Point	Carotid body	Aortic body
Site	carotid bifurcation	ascending aorta and arch
Afferent nerve	glossopharyngeal (IX)	vagus (X)
Sensor cells	glomus cells	similar glomus cells
Role in breathing	main peripheral sensor	weaker; responds a little differently

Draw it: the carotid body

Draw the common carotid splitting into internal and external carotids, and label the swelling at the start of the internal carotid “carotid sinus”. Put a small oval at the fork and label it “carotid body”. In a magnified circle beside it, draw a cluster of round type I (glomus) cells, flat type II cells wrapped around the cluster, fenestrated capillaries hugging it, and a glossopharyngeal nerve ending touching one glomus cell. Label that contact “dopamine → D2 receptor”.

Sensitivity of chemoreceptors

• The receptors respond to hypoxia, hypercapnia and acidosis, and they work differently from ordinary sensory receptors.
• The glomus cell senses all three.
• Common final path:
  1. K⁺ channels are inhibited;
  2. the cell depolarises;
  3. voltage-gated Ca²⁺ channels open;
  4. transmitter is released and the afferent nerve fires.
• Only the way each stimulus shuts the K⁺ channels differs:

Stimulus	How K⁺ channels are shut
Hypoxia	O₂ sensor, cAMP, glutathione (below)
Hypercapnia	CO₂ makes H⁺ inside the cell
Acidosis	Na⁺–H⁺ exchanger blocked, H⁺ builds up

Hypoxia

Hypoxia is the main stimulus for the peripheral chemoreceptors. With blood pH and PCO₂ normal:

PO₂	Response
above normal	no real change in breathing
below 100 mmHg	afferent firing rises steadily
below 80 mmHg	ventilation clearly rises
below 60 mmHg	strongest; curve steep, near linear

• So the ventilatory response is not linear over the whole range.
• In the classic experiment, alveolar PCO₂ was held at 43 mmHg by adding CO₂ to the inspired air. Without that, the low PCO₂ caused by the extra breathing would have damped the response.

Why breathing rises so little between 100 and 60 mmHg:

1. Less H⁺: oxy-Hb is a stronger acid than deoxy-Hb. As Hb gives up O₂, arterial H⁺ falls slightly, and a fall in H⁺ restrains breathing.
2. Less CO₂: the extra breathing blows off CO₂, and the lower PCO₂ also restrains breathing.

Only below about 60 mmHg is the hypoxic drive strong enough to override both brakes.

• Worth knowing, though not in your pages: 60 mmHg is about where the flat top of the dissociation curve ends (Hb still about 90% saturated). Above it, the O₂ content of blood hardly falls.

Applied: why anemia and CO poisoning don't make you breathe harder

The peripheral receptors respond to PaO₂, not to O₂ content. In anemia and carbon monoxide poisoning the blood carries less O₂ but its PaO₂ is normal, so the ventilatory response barely changes.

How hypoxia fires the glomus cell. Hypoxia shuts K⁺ channels, the cell depolarises, Ca²⁺ enters through voltage-gated channels and transmitter is released onto the afferent nerve. The K⁺ channels may be shut in three ways:

1. O₂-sensing heme protein: a heme-containing protein sits beside the K⁺ channel and normally carries O₂. When it loses that O₂ in hypoxia, the channel is inhibited.
2. cAMP: hypoxia raises cAMP in the glomus cell, which closes cAMP-sensitive K⁺ channels.
3. Glutathione: hypoxia inhibits mitochondrial NADPH oxidase. The ratio of reduced (GSH) to oxidised (GSSG) glutathione rises, and that directly inhibits K⁺ channels.

Effect of alveolar PCO₂ on the hypoxic response:

Alveolar PCO₂	Hypoxic response
37 mmHg (low)	none until PO₂ is below 60, then steep
49 mmHg (high)	graded: each fall in PO₂ raises ventilation

So the CO₂ level decides how far hypoxia can drive breathing.

Hypercapnia

• Carotid and aortic firing rises linearly with PaCO₂, and ventilation rises with it.
• Metabolism makes CO₂, so more metabolism means more breathing, which clears the extra CO₂. Ventilation stays up until PaCO₂ is back to normal.
• The real stimulus is H⁺: CO₂ entering the glomus cell forms H₂CO₃, and its H⁺, not the CO₂ molecule, excites the cell.
• The peripheral receptors carry up to 40% of the effect of PaCO₂ on breathing; the rest is central.

Which receptor for which gas?

Hypoxia acts mainly through the peripheral chemoreceptors; hypercapnia acts mainly through the central chemoreceptors. Swapping these is the commonest mistake in this topic.

Breathing a CO₂ mixture:

1. Alveolar PCO₂ rises, arterial PCO₂ follows, and ventilation increases.
2. The extra breathing removes some CO₂, but alveolar PCO₂ never gets back to normal while the mixture is breathed, so ventilation stays high.
3. Ventilation rises almost linearly with alveolar PCO₂ (measured with alveolar PO₂ held at 100 mmHg).
4. Once inspired CO₂ passes 7%, alveolar and arterial PCO₂ shoot up: CO₂ can no longer be cleared and piles up in the blood.

Applied: CO₂ narcosis

Very high PCO₂ depresses the brain instead of driving breathing. Headache and confusion come first, and coma follows quickly. See Asphyxia, hypercapnia and hypocapnia.

How CO₂ fires the glomus cell:

1. More CO₂ enters the cell and forms H⁺, so the pH inside falls.
2. H⁺ blocks K⁺ channels, and K⁺ efflux stops.
3. The cell depolarises and voltage-gated Ca²⁺ channels open.
4. Ca²⁺ entry releases transmitter, and firing in the glossopharyngeal nerve rises.

Effect of hypoxia on the CO₂ response: the lower the alveolar PO₂, the steeper the CO₂ response curve and the further it shifts left. Hypoxia makes breathing more sensitive to CO₂.

Draw it: the two response curves

Draw two graphs with ventilation on each y-axis. On the first, put alveolar PO₂ on the x-axis (0 to 120 mmHg): the line is almost flat from 120 down to about 60, then climbs steeply as PO₂ falls further; write “PACO₂ held at 43 mmHg”. On the second, put alveolar PCO₂ on the x-axis: draw a straight rising line labelled “normal PAO₂”, and a steeper line to its left labelled “hypoxia”.

Acidosis

• Peripheral receptors respond to a fall in arterial pH.
• Acidosis alone, with no hypoxia or hypercapnia, stimulates breathing, as in metabolic acidosis.
• It also makes the receptors more sensitive to PaCO₂.
• Mechanism: a low pH blocks acid-extruding transporters such as the Na⁺–H⁺ exchanger. H⁺ builds up inside the glomus cell and inhibits K⁺ channels.

Other factors

• Cyanide, and other poisons of the respiratory chain, strongly stimulate the peripheral chemoreceptors.
• A fall in blood pressure below 60 mmHg stimulates them, whether or not PaO₂ changes. This acts mainly through the aortic bodies.
• Their signals mix with those of other reflexes, such as the lung stretch and baroreceptor reflexes, to regulate heart and breathing together.

Central chemoreceptors

• Site: paired cell groups on both sides, just beneath the ventrolateral surface of the medulla, immediately caudal to the pontomedullary junction. Also called medullary chemoreceptors or chemosensitive areas.
• Each side has three zones, named after the physiologists who described them:

Zone	Described by
Rostral	Mitchell
Intermediate	Schläfke
Caudal	Loeschcke

• They respond to H⁺ in the surrounding interstitial fluid. That H⁺ depends on the PCO₂ of cerebral arterial blood and the bicarbonate of the CSF.
• More recently, chemosensitive neurons have also been found in or near the NTS, nucleus ambiguus, locus ceruleus and hypothalamus.

Mechanism of stimulation

• CSF chemistry: almost free of protein, with less phosphate than plasma but about the same bicarbonate. So bicarbonate is the main buffer of CSF.

1. Blood H⁺ enters the brain very slowly, so a change in blood H⁺ barely shows in the CSF.
2. CO₂ crosses freely. In CSF it is hydrated at once to H₂CO₃, which splits into H⁺ and HCO₃⁻.
3. So brain interstitial H⁺ tracks arterial PCO₂, and the receptors fire in proportion to that H⁺.

Fluid	pH
CSF	7.3
Blood	7.4

CSF pH is set by the bicarbonate and PCO₂ of the CSF. That is why it follows some disturbances closely and others only partly:

Disturbance	CSF bicarbonate change	CSF pH change
Metabolic	about 40% of blood’s	smaller than blood’s
Respiratory	same as blood’s	same as blood’s

The receptor feels H⁺, not CO₂

The central chemoreceptors respond to H⁺. CO₂ drives them strongly only because it enters the brain at once and makes H⁺ there, while blood H⁺ itself barely gets in.

Integrated responses

In real life hypoxia, hypercapnia and acidosis rarely occur alone. Hypoxia usually comes with hypercapnia and acidosis, and both receptor sets fire together.

• Hypoxia and hypercapnia boost each other:
  • the CO₂ response is larger in hypoxia, the more so the deeper the hypoxia;
  • the hypoxic response is larger when PaCO₂ is high.
• The catch: the extra breathing lowers PaCO₂, and a low PaCO₂ blunts the hypoxic response, mainly through the central receptors. The full hypoxic response shows only if PaCO₂ is held constant.
• High altitude is the best example. Hypoxia drives the peripheral receptors and breathing rises; the respiratory alkalosis that follows then weakens the hypoxic drive. See Acclimatization to high altitude.
• H⁺ and CO₂ add together: a lower pH makes the receptors more sensitive, so the CO₂ response curve shifts left. If CO₂ were prevented from lowering arterial pH, about 40% of the response to CO₂ would be lost.

These interactions show most clearly in metabolic and respiratory acidosis.

Metabolic acidosis

It is caused by non-volatile acids such as lactic acid and keto acids.

1. Early: H⁺ drives the peripheral receptors and breathing rises. The central receptors are not driven directly, because blood H⁺ barely enters the CSF.
2. The extra breathing lowers PaCO₂, so CSF pH actually rises.
3. This paradoxical CSF alkalosis holds the hyperventilation back.
4. Over days, CSF bicarbonate is adjusted downward, the alkalosis disappears, and the central receptors add their drive, so breathing rises further.
5. The result is deep, heavy breathing, such as Kussmaul breathing in diabetic ketoacidosis (Abnormal breathing patterns).

Respiratory acidosis

It is caused by retained CO₂. Common causes:

• Chronic obstructive lung disease: emphysema, asthma.

• A failing respiratory pump: muscle weakness from myopathies and neuropathies.

• Centers that stop responding to CO₂: anesthesia, brain injury.

• Acute phase: minute ventilation rises in step with PaCO₂.

• After a few days: CSF bicarbonate rises in compensation, CSF pH rises and the CO₂ response curve shifts right. Ventilation falls back: central adaptation.

• So in chronic lung disease the central CO₂ drive is weak, even though hypercapnia persists. Breathing is kept going by hypoxia acting on the peripheral receptors.

Applied: oxygen in chronic hypercapnia

Give such a patient oxygen alone and the hypoxic drive disappears. Breathing falls further, CO₂ climbs and the acidosis worsens. The better answer is mechanical support to restore ventilation. See Oxygen therapy.

Hormonal control

• Progesterone stimulates breathing, so ventilation is clearly higher in pregnancy and in the secretory phase of the menstrual cycle.
• It is thought to act on the medullary centers. It also raises body temperature, which itself drives breathing.
• Thyroxine, cortisol and catecholamines influence breathing too.

Exam-answer skeleton: "Describe the chemical regulation of respiration" (long essay)

1. The stimuli (PCO₂, H⁺, PO₂), the direction of each effect, and the two sets of receptors.
2. Peripheral chemoreceptors: carotid body site, size, blood flow, type I and II cells, nerve; aortic bodies (diagram).
3. The common glomus-cell mechanism: K⁺ channels shut → depolarisation → Ca²⁺ entry → transmitter release.
4. Hypoxia: the 100, 80 and 60 mmHg steps, why the rise is small down to 60, the three K⁺-channel mechanisms, and anemia and CO poisoning (curve).
5. Hypercapnia: linear response, H⁺ as the real stimulus, up to 40% peripheral, the 7% limit and CO₂ narcosis (curve).
6. Acidosis, and the other stimuli (cyanide, BP below 60 mmHg).
7. Central chemoreceptors: site, three zones, how CO₂ acts through CSF H⁺, CSF against blood pH.
8. Integration: how the stimuli interact, metabolic and respiratory acidosis, oxygen in chronic hypercapnia; hormones.

Asked in exams

• Chemical control of breathing and the chemoreceptors: Jul 2011, 2 marks · Aug 2016, 4 marks · Jul 2018, 2 marks · Jul 2019, 10 marks · Oct 2024, MCQ