In regulating breathing, central nervous mechanism integrate information about a large number of physical, chemical and nervous variables. The chemical changes in arterial blood involving its PCO₂, PO₂ and pH have a profound effect upon respiration. Two types of specialized nerve endings are of importance in this connection. These are given below:

1. Chemosensitive receptors in the Medulla Oblongata
2. Chemosensitive receptors in the carotid and aortic bodies; these are called peripheral chemoreceptor.

   Medullary Chemosensitive Receptors

The nerve endings are present in the ventrolateral surface of medulla where they lie quite superficially. The area of the medulla containing these receptors is bounded rostrally by the pons, laterally by the roots of the 7th to 11th cranial nerves and medially by the pyramidal tracts; it extends caudally by 6 to 7 mm. This area is therefore quite distinct from the respiratory center. When a pledget soaked in cerebrospinal fluid saturated with CO₂ or soaked in an acidic solution is applied to this area, an immediate response showing hyperpnea (increased respiration) results. Application of drugs like acetylcholine and nicotine to this area also results in hyperpnea. On the other hand, an application of procaine, a local anesthetic agent, or cold which depress nerve activity of this area results in a cessation of breathing or apnea. These methods have been used to localize the chemosensitive area of the brain stem.

The primary stimulus for chemosensitive receptor is a fall in the pH of extracellular fluid which lies close to the surface of the brain. The extracellular fluid in this region resembles the cerebrospinal fluid with which it freely communicates in respect to HCO₃- and CO₂. The PCO₂ of the arterial blood serves to regulate the pH of the extracellular fluid in this area. A rise in the arterial blood PCO₂ leads to a greater CO₂ diffusion into the cerebrospinal fluid and the extracellular fluid thus reducing their pH leading to an increased ventilation of the lungs or hyperpnea. The fall in arterial blood PCO₂ has the reverse effect, i.e. there is a rise in the pH causing a decrease in pulmonary ventilation.

Experiments on human beings have shown that breathing 4% CO₂ increases pulmonary ventilation to twice the normal value. Breathing 10% of CO₂ increases pulmonary ventilation to 10 time the normal value. The maximum effect on pulmonary ventilation is produced by breathing about 20% of CO₂. Any further increase in CO₂ results in lowering of pulmonary ventilation. At 10% CO₂, dyspnea, headache, faintness, and restlessness are produced. At 15% CO₂ there result rigidity of muscles, tremors and convulsions and the subject may lose consciousness. Breathing 20% CO₂ results in surgical anesthesia.

A fall in arterial blood PO₂ (Hypoxia) leads to a depression of the activity of the medullary chemosensitive area as well as that of the respiratory center.

   Peripheral Chemoreceptors

These lie in the carotid and aortic bodies. The carotid body is a small pinkish nodule located in the bifurcation of the common carotid artery. It is the most vascular tissues in the body receiving every minute 20 ml of blood per gram of tissue. The blood on flowing through it comes in contact with nerve endings sensitive to chemical changes in the blood. The afferent nerve fibers travel in the carotid branch of the glossopharyngeal nerve which also carries afferents from the stretch receptors present in the carotid sinus.

The aortic bodies are groups of cells resembling cells of the carotid bodies; these are situated in the aortic arch. The afferents from these bodies travel via the aortic nerves.

The most effective stimulus to peripheral chemoreceptor is a fall in arterial PO₂ (hypoxemia). A rise in PCO₂ and fall in pH of the arterial blood can also stimulate these chemoreceptors but to a much lesser extent than hypoxemia. The stimulation of peripheral chemoreceptors results in a reflex hyperpnea. If the peripheral chemoreceptors are denervated or their afferent never fibers blocked by a local anesthetic agent, then the reflex hyperpnea is not obtained. The carotid body has 7 times more chemoreceptor activity than the aortic bodies.

In addition to the above mentioned chemical changes in the arterial blood, i.e. fall in PO₂ and pH; and rise in PCO₂, some other changes in blood also stimulate chemoreceptor activity.

These are the following:

1. Cyanide: This acts by inhibiting cytochrome oxidase which produces hypoxia within chemorecptor tissue by a non-utilization of O₂.
2. Nicotine: It stimulates sympathetic ganglion cells.
3. Acetylcholine, lobeline, serotonin and sulfides
4. Raised temperature of blood.
5. Decreased blood flow through carotid and aortic bodies.

There is some tonic chemoreceptor activity even at an arterial PO₂ of 100 mm Hg. But most of the chemoreceptors are stimulated when alveolar PO₂ falls to 40-50 mm Hg. This takes place when O₂ in the breathed air falls to below 14%. Thus no increase in pulmonary ventilation occurs unless O2 concentration is decreased to less than 14% although cyanosis and some subjective discomfort may be observed.

   Effects of stimulation of Peripheral Chemoreceptors

1. An increase in pulmonary ventilation.
2. Vasoconstriction in limb vessels.
3. Bradycardia: This is due to vagal activity.
4. Rise in blood pressure which may however be masked by bradycardia.
5. Increased bronchiolar tone
6. Increased pulmonary vascular resistance
7. Increased secretion of hormones of adrenal medulla and cortex.
8. Increased activity of the motor cortex.

As mentioned above, a change in the pH of the arterial blood can also affect pulmonary ventilation through its effect on peripheral chemoreceptors. However, the peripheral chemoreceptors are not very sensitive to changes in pH as seen by fact that a fall of 0.1 unit in the pH (which is quite a marked change) is required for producing their stimulation.

The two main points in the chemical regulation of respiration are given below:

1. The peripheral and central inputs are integrated in the central nervous system and control the breathing movements in such a way that the O₂, CO₂ and acid-base characteristics of the internal environment of the body tend to be stabilized.
2. Pulmonary ventilation is very sensitive to changes in arterial blood PCO₂ which act through the medullary chemosensitive receptors. On the other hand, the respiratory mechanism is relatively less sensitive to changes in arterial blood PO₂ and pH which act through peripheral chemoreceptors. It should be noted that although peripheral chemoreceptors are not of much importance under physiological conditions but in certain pathological conditions they may assume a much greater importance in this condition.

   Breath Holding

If a subject voluntarily stops his breathing at end of expiration, the subject can maintain his apnea for short time, i.e. upto one minute or less, at the end of which he is forced to start rebreathing. This restart of breathing is brought about by the following two factors:

1. During the voluntary apnea O₂ present in the alveolar air (still) continues to oxygenate Hb; this results in a fall in the alveolar PO₂ which leads to a fall in the arterial blood PO₂ or hypoxemia. This stimulates the peripheral chemoreceptors.
2. The arterial PCO₂ starts rising because the elimination of CO₂ in the lungs is decreased; the medullary chemoreceptors are stimulated.

If the subject, before holding his breath, hyperventilates for some time he becomes able to hold his breath for a longer time. This is because hyperventilation results in a fall of arterial blood PCO₂ which thus is low at the start of the voluntary apnea. On the other hand, hyperventilation does not result in any increase in the arterial blood PO2 because the blood is almost completely saturated with O₂ even during the normally slow respiration. Therefore, in this case the stimulus for rebreathing is only hypoxemia in the early phase.

Breathing starts but it again stops after a few breaths which are sufficient to remove hypoxemia. Again when the arterial blood PO₂ falls, there is a restart of breathing followed by another period of apnea which however is smaller than the first. This periodic breathing which is called Cheyne-Stokes breathing, continues for some time until the arterial blood PCO₂ again becomes normal and restarts normal breathing pattern by its action on medullary chemoreceptors.

Hyperventilation with O₂ instead of air enables a person to hold his breath for a still longer period. In this case the alveolar PO₂ is greatly raised and thus the production of hypoxemia takes a longer time to develop. As both stimuli needed for restarting breathing, i.e. hypoxemia and an increased arterial blood PCO₂, take more time to develop, therefore the person can hold his breath for a much longer time.