Chemical Regulation of Respiration: Role of Chemoreceptors and Reflexes

Chemical regulation of respiration is made by chemoreceptors present in the body. The chemoreceptors present in the body can be divided into two groups:

• Peripheral chemoreceptors.
• Central chemoreceptors.

• Peripheral chemoreceptors are located at the level of the carotid body and aortic body.
• In the diagram, there is a depiction of the common carotid artery divided into the internal carotid artery and the external carotid artery.
• At the origin of the internal carotid artery, the dilated area is known as the carotid sinus.
• At the bifurcation of the internal and external carotid arteries, the tennis racket-shaped small tissues are known as carotid bodies. These carotid bodies are the chemoreceptors.
• When looking at the arch of the aorta, on the surface of the arch of the aorta, 2-3 tennis racket-shaped small structures are present, known as aortic bodies.
• The aortic bodies and carotid bodies are the peripheral chemoreceptors.
• In this same area, the baroreceptors are also located.
• Chemoreceptors are located within the aortic bodies and carotid bodies.

Mechanism of the Activation of the Glomus Cell

• A diagram of the glomus cell type 1 is depicted. It is activated by hypoxia.
• The glomus cell contains an ion channel and an oxygen-sensitive potassium channel.
• If oxygen-sensitive potassium channels are open, potassium goes out of the cell.
• When the oxygen tension in the arterial blood is normal, potassium goes out of the cell normally.

Low O2 tension in arterial blood (hypoxia)

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Inhibit the O2 sensitive K+  – channel by causing its closure.

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K+ stays back in the cell, since K+ is positively charged.

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↑↑ positive charges collected inside the cell membrane.

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Depolarisation of the cell

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A voltage-gated Ca++ channel is activated inside the glomus cell in the presence of depolarization.

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The channel opening causes calcium to enter.

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The glomus cells are secretory cells containing multiple vesicles with various neurotransmitters.

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Ca++ enters the cell; these vesicles move closer toward the cell membrane.

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Vesicular membrane and plasma cell membrane fuse, leading to the rupture of the area.

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On rupture, the neurotransmitters present in the vesicles will be released.

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The neurotransmitters cause activation of the 9th and 10th cranial neurons that are connected.

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Action potential is generated. 

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Action potential travels to the pre-Bötzinger complex, causing an increase in ventilation. That is, both the rate and depth of respiration will be increased.

• In the presence of hypoxia, when the peripheral chemoreceptors are stimulated, there is an increase in ventilation/hyperventilation.

Also read: Comprehensive Overview Of Lung Pathology Images

Central Chemoreceptors

Central chemoreceptors are located on the ventral medullary surface just beneath the surface.

In the diagram, the cross-section of the medulla can be seen.

• It is surrounded by the cerebrospinal fluid (the CSF region).
• At the ventral medullary surface, there are certain neuronal groups called chemo-sensitive neurons.
• These neurons are central chemoreceptors.
• The Glomus cell is not there in the medulla.
• Chemo-sensitive neurons detect certain chemicals in the medullary region known as the chemosensitive zone.
• These neurons cannot detect hypoxia.
• Thus, the main stimulus for central chemoreceptors is the H+ ion of the cerebrospinal fluid or the interstitial fluid of the brain.
• The stimulating H+ ion has to be present in the CSF or surrounding the neuron (the interstitial fluid of the brain).

Applied Aspects of Chemoreceptors

1. In the case of COPD patients → chemoreceptor sensitivity decreases.

• In the case of emphysema or COPD patients, decreased sensitivity or desensitization of chemoreceptors will stop the CO2 from stimulating the peripheral chemoreceptors. 
• This causes the accumulation of CO2 in the body of COPD patients. 

2. Voluntary hyperventilation in the body

• During voluntary hyperventilation, more fresh oxygen enters the body, and more and more CO2 will wash out from the body, causing alkalosis, which inhibits the peripheral chemoreceptors of the body.
• This will cause a temporary stoppage of respiration or apnoea. The CO2 will start its accumulation in the body, thereby starting respiration again.

Also read: Cell Physiology: Overview of Membrane, Cytoskeleton &

Stimulation of Chemoreceptors by Hypercapnia and Hypoxia

• Now the stimulating pattern of how the carbon dioxide or oxygen, or how hypercapnia and hypoxia are stimulating the chemoreceptors, is discussed.
• A graph is drawn; the x-axis represents carbon dioxide (PCO2), and the y-axis represents ventilation.

• When the CO2 rises more and more in the arterial blood, there will be an increase in ventilation.
• A person is given an inhalation of 2%, followed by 3%, followed by 4%, followed by 5% CO2
• Which of the following curves will be seen in this person?
• When a person is given more and more CO2, there will be more and more ↑ ventilation in a linear fashion.
• Normal: PCO2 in the arterial blood is 40; if PCO2 rises from 40 to 60, eventually to 80. 
• In such a case, ventilation will rise more and more; hence, both the depth and rate will increase.
• This increase in ventilation will continue until a CO2 value of 80 mm Hg is reached. 
• When the PCO2 is beyond 80, a further increase in ventilation will not be possible. Rather, there can be depression of ventilation.
• This condition is observed in deep-sea divers whenever the gas is inhaled at high pressure, and the arterial blood's carbon dioxide partial pressure also increases.
• If PCO2 is beyond 80 mm Hg, rather than stimulation of the peripheral chemoreceptors, it causes depression of the peripheral chemoreceptors.
• So, from 40 mm Hg to 80 mm Hg, the increase in ventilation is linear.
• If the carbon dioxide percentage is doubled, the ventilation will also be doubled. This is the meaning of a linear relationship. This relationship is maintained up to 80 mm Hg.
• If the CO2 percentage is decreasing in the arterial blood, a point can be found where the CO2 is so low that the ventilation is 0. It is touching the x-axis.
• This means that ventilation is stopped for a certain period, and apnea takes place. This point is known as the apnea point.

Also read: Biostatistics Multiple-Choice Questions for Health Sciences

Herring-Breuer Reflex

Hering-Bruer inflation reflex

• Prevents further inflation of the lungs during deep breaths (inflation).
• Activated by stretch receptors in lung smooth muscles (bronchi and bronchioles).
• Stretch receptors activated → Tidal Volume (TV) > 1L
• Stretch receptors: Slow-adapting type of receptors.
• Inflation of the lungs during deep breathing (TV > 1L) activates the vagus neuron (myelinated fibres of the vagus).
• Vagus neuron inhibits inspiratory neuron, preventing further inspiration and lung expansion.
• Vagus neuron (myelinated fibre of the vagus nerve).

Hering-Bruer Deflation Reflex

• Strong deflation prevents further deflation, safeguarding against lung collapse.
• Triggered by strong deflation of the lungs.
• Involves proprioceptors at the level of respiratory muscles and bones.
• Reaches a point where deflation prevents further collapse of the lungs.
• Prevents further deflation, ensuring lung integrity.

Heads Paradox Reflex

• This reflex was first described by Henry Heads in 1884.
• The paradox could be understood when this reflex is compared with the Hering-Breuer reflex.
• It is said that inflation of the lung stimulates further inflation; this is the Heads paradox. This can lead to rupture of the lung.
• This reflex is not seen in the adult lung; this is seen in the first cry of a newborn.
• When a newborn takes the first gasp of respiration through the first cry, there will be continuous inflation until the lung's water is squeezed out.

Also read: Neural Regulation of Respiration: Control & Mechanisms

J-Receptor Reflex

• It is also known as the C-fibre receptor reflex.
• In neuronal classification, there are A, B, and C fibres. C fibre is the unmyelinated nerve fibre.
• The afferent from the J-receptor is also the vagus, but it is the unmyelinated fibre of the vagus, which is the C fibre. Hence it is also known as the C-fibre receptor reflex. J stands for juxta capillary receptors.

Response on J-Receptor Activation

• Hyperventilation
• Apnoea (rapid, shallow breathing)
• Bronchoconstriction
• Increased mucous secretion
• Decreased blood pressure and Heart rate
• All these conditions ultimately lead to Dyspnoea

Important Questions 

Q. Chemoreceptors are due to which of the following cells?

Ans. Type 1 glomus cells.

Q. What are the activators of the sensor cells? What are the chemicals that they can sense?

Ans. The chemicals that they can sense are as follows:

1. Decrease in partial pressure of the oxygen in the arterial blood, also called hypoxia.

2. Increase in partial pressure of carbon dioxide in the arterial blood, also called hypercapnia.

3. Increase in H+ ions in the arterial blood, also called acidosis.

• So, hypoxia, hypercapnia, and acidosis are the dominant stimulants of the peripheral

chemoreceptors for both aortic bodies and carotid bodies.

• But the chemoreceptors for carotid bodies are more sensitive than the chemoreceptors for aortic bodies.

• Type 2 glomus cells surround and protect the type 1 glomus cells and are known as supporting cells or sustentacular cells.
• When chemical stimulators are present such as hypoxia, hypercapnia, and acidosis, the type 1 glomus cells will be activated, and certain neurons that are the 9th and 10th cranial nerves at the level of the glomus cell will be activated.
• At the aortic region, the connected cranial nerve is the vagus nerve (X cranial nerve).
• At the carotid region, the cranial nerve that is connected is the Glossopharyngeal nerve (IX cranial nerve)
• IXth and Xth cranial nerves are afferent neurons from the chemoreceptors.
• When chemoreceptors are activated, they stimulate the afferent neurons connected with the glomus cells.
• These afferent neurons stimulate the ventilatory center or the respiratory center, the pre-Bötzinger complex.

Also read: Hyponatremia: Classification, Signs & Symptoms

Q. What is the main neurotransmitter released by the glomus cell?

Ans. 

• Ganong states that the main neurotransmitter released by the glomus cell is dopamine, but that is not correct.
• According to recent medical literature, particularly Guyton, adenosine triphosphate (ATP) is the main neurotransmitter released by the glomus cell. This is followed by acetylcholine and dopamine.
• Hypercapnia and acidosis act in quite similar manners.
• Hypercapnia and acidosis cause the closure of the O2-sensitive K+ channel, but this is done by a sudden indirect mechanism.
• Hypercapnia and acidosis activate certain molecules present inside the cell in the form of a second messenger, and these second messengers cause the closure of the O2 - sensitive K+ channel. 2
• Since the O2-sensitive K+ channel is sensitive to oxygen, hypoxia can directly cause the closure. 
• Hypoxia causes a direct effect,
• Hypercapnia and acidosis cause an indirect effect that leads to the closure of the O2 - sensitive K+ channel

Q. Which is the primary or direct stimulus of the peripheral chemoreceptors?

Ans. Hypoxia is the primary or direct stimulus of the peripheral chemoreceptors.

Q. Which is the most sensitive stimulus of the peripheral chemoreceptors?

Ans. When 1% tension of oxygen is changed, 1% tension of carbon dioxide is changed, and 1% tension of H+ ion is changed, the most sensitive stimulus is 1% change of tension of carbon dioxide. This is hypercapnia.

Q. Which is the most potent stimulus of the peripheral chemoreceptors?

Ans. The most potent stimulus of the peripheral chemoreceptors will be cyanide poisoning. This is caused by histotoxic hypoxia.

Q. If a person has ascended to a high altitude, there will be hypoxia and hyperventilation. The chemoreceptors will be stimulated. But hyperventilation in high altitude is due to which kind of chemoreceptors?

Ans.

• It is only peripheral chemoreceptors and not the central chemoreceptors because hypoxia is a stimulus for the peripheral and not the central chemoreceptors.
• Suppose there is ↑ H+ ions in the plasma (acidosis).

Q. Can acidosis stimulate central chemoreceptors?

Ans. Central chemoreceptors can be stimulated by H+ ions present at CSF or the interstitial fluid of the brain.

Q. Can the H+ ion of the blood reach up to the level of the chemo-receptor neuron?

Ans. No, because this H+ ion is an ionic molecule.

Also read: Hypernatremia: Causes, Pathophysiology

Q. Can an ionic molecule penetrate through the level of the brain capillary?

Ans. It cannot because a strong barrier, the blood-brain barrier, protects the brain capillary.

• Thus, the H+ ion of the blood cannot reach up to the level of the chemoreceptor.
• Acidosis stimulates only peripheral chemoreceptors
• Acidosis cannot stimulate central chemoreceptors because of Blood-Brain Barrier

• The third stimulus for the peripheral chemoreceptors was hypercapnia.
• ↑CO2 in the blood can cross the blood-brain barrier because it is a gaseous molecule, and it will thus reach the brain interstitial fluid.
• It can also penetrate the CSF, where the CO2 will react with the water, producing carbonic acid. 
• This acid will be divided into H+ ions and bi-carbonic ions. Now the H+ ion will stimulate the central chemoreceptors.
• Thus, the CO2 stimulates the central chemoreceptors through the production of H+ ions at the level of  CSF.
• The CO2 stimulates the peripheral chemoreceptors as well. 
• 80% of the carbon dioxide goes to the central chemoreceptors, and 20% goes to the peripheral chemoreceptors for stimulation.

Q. If a person is hyper-ventilating due to hypercapnia, what is the main stimulus?

Ans.

· Central chemoreceptor is the main stimulus. Among the three stimuli, carbon dioxide is the main stimulus. Peripheral chemoreceptor is also stimulated, but only 20%.

Q. If during voluntary hyper-ventilation, if the person inhales 5% carbon dioxide, what happens?

Ans.

• During voluntary hyper-ventilation, the person inhales 5% Co2 . 
• With each inhalation, more CO2 content in the body rises. 
• So, when there is inhalation, along with atmospheric air, extra amounts of CO2 enter the body. Thus, instead of the CO2 washing out, CO2 content in the body does not decrease. In such a case, no apnoea will occur.

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