When we think of respiration, we think of an automatic, involuntary activity, that brings enough air into the pulmonary alveoli to maintain the O2 and CO2 tensions of alveolar gas or arterial blood at optimal levels in different conditions: rest, sleep or exercise. The optimal gas exchange must be controlled by the central neuronal complex, able to integrate all information coming from the periphery and in return to give adequate depth and frequency of breathing (minute ventilation). But respiration, unlike other involuntary activities is also under voluntary control. We can stop or increase breathing voluntarily. We can use expiratory air to speak or sing. Anatomically, there are separate neurologic structures for automatic and voluntary control, although the two systems interact. The cerebral hemispheres control voluntary breathing and can be effective even when automatic control no longer functions.

If you stop ventilation voluntarily, you will find out that in spite of your efforts to prevent it, breathing will eventually start again. This is called the breaking point, which normally occurs at PaO2 around 70 mmHg and PaCO2 around 50 mmHg. This suggests that the voluntary control of breathing is over-ridden by the automatic control and that the latter depends on the information from receptors sensitive to CO2 and O2 levels (in arterial blood and/or cerebro-spinal fluid).


The neuronal structures involved in control of breathing are located in the brain stem (pons and medulla). Like in other physiological systems in the respiratory control system, there are three basic elements. These are schematically illustrated in Fig. 16. Sensors gather information about lung volume (pulmonary receptors) and O2 and CO2 content (chemoreceptors). This information is sent by afferent neural fibres to the central controller located in the pons and the medulla. There, the peripheral information and inputs from the higher structures of the central nervous system is integrated. And finally as a result of this integration, neuronal impulses are generated and sent through the spinal motoneurons to the effector, i.e., the respiratory muscles. This in turn causes ventilation which is adjusted to the patient's metabolic demands. Since, the main function of the lungs is to exchange O2 and CO2 between alveolar gas and blood, whenever the demand for O2 and production of CO2 increase (as during exercise), ventilation must increase too, to satisfy this requirement.


Fig. 17. Dorsal view of the brain stem with indicated location of the dorsal (DRG) and ventral (VRG) group of respiratory neurons. DRG is located in the area of the nucleus tractus solitarius. VRG includes nucleus ambigualis and retroambigualis.The pons is confined between lines A and C. The medulla is indicated by lines C and D. NPBL, in the upper pons, stands for  nucleus parabrachialis lateralis the site of the pneumotaxic mechanism.  IV: the 4th ventricle.

Fig. 17 schematically illustrates the brainstem with localization of respiratory neurons.  In the medulla, respiratory neurons are concentrated mainly in two locations, i. e. the dorsal respiratory group (DRG) and the ventral respiratory group (VRG).
The pons is confined between A and C lines. The medulla is located below the pons, lines C and D make its border. NPBL in the upper pons stands for the nucleus parabrachialis lateralis the site of the pneumotaxic mechanism. In anesthetized animals, lesions in these areas or section of rostral pons (indicated in fig. 17 by B) cause a deep and slow pattern of breathing. In anesthetized animals with vagi cut, elimination of the pneumotaxic mechanism causes prolonged inspirations followed by short expirations. This respiratory pattern is called apneustic breathing.

Respiratory neurons are active either during inspiration or expiration. Their descending axons go to the phrenic motoneurons at the spinal level (the phrenic nerve innervates the diaphragm) and to the spinal motoneurons of other inspiratory and expiratory muscles. The muscle contraction depends on the amount of neuronal activity reaching their motor units. The amount of the respiratory activity generated at the medullary level depends on incoming information from the sensors, the chemoreceptors, vagal pulmonary receptors and a variety of other inputs (Fig. 18). Whenever chemoreceptor activity increases, the motor output to respiratory muscles increases.


Fig. 18.  Diagram illustrating automatic regulation of respiration. Respiratory neurons in the medulla discharge during inspiration or expiration but activity of some neurons overlaps the end or the beginning of either phase of the respiratory cycle. The respiratory neurons are under influence of activity arising in chemoreceptors and mechanoreceptors. Chemoreceptors : central, respond to increased PCO2 in the cerebro-spinal fluid, and peripheral, respond to low PO2 but also to increased PCO2 in arterial blood. Mechanoreceptors: stretch receptors in the respiratory and other postural muscles, and mainly vagal slowly adapting stretch receptors (SAR) located in the lungs. Their activity increases with increasing lung volume.  Neuronal activity controls contractions of the respiratory muscles. Stronger contraction of the diaphragm the greater lung volume. Inhaled air, due to convection and diffusion, reaches alveoli. Perfused alveoli contribute to gas exchange (diffusion of O2 from, and CO2 to the alneoli). The level of blood gases and pH are detected by chemoreceptors. Increased PCO2 or decreased PO2 leads to stimulation of chemoreceptors. Consequently, neuronal activity, contraction of respiratory muscles, and therefore, ventilation increase. Ventilation remains increased as long as the blood gases are not corrected.


PO2, PCO2 and pH in arterial blood or cerebrospinal fluid are detected by the chemoreceptors. If these pressures or pH are changed, ventilation will also change in an attempt to bring the gas pressures to the normal values. The PO2, PCO2 and pH changes are sensed by the chemoreceptors. Information from chemoreceptors is carried to the respiratory neurons. In turn, the activity of respiratory neurons will increase if PaO2 is too low (less than 60 mmHg) or PaCO2 is higher than 40 mmHg.  Activity of the respiratory neurons will decrease if PaO2 is higher than 100 mHg or PaCO2 is lower than 40 mmHg. There are two groups of chemoreceptors: central and peripheral . Central chemoreceptors (Fig. 19) are located at the ventral surface of the medulla and detect pH of the cerebrospinal fluid surrounding them (PCO2 and pH of the cerebrospinal fluid are influenced by those of arterial blood).

Fig. 19. Brainstem with sketched locations of the central chemoreceptors on the ventral surface of the medulla. Cranial nerves are indicated by roman numerals.

Peripheral chemoreceptors are mainly sensitive to changes in PO2, but are also stimulated by increased PCO2 and decreased pH. They are located in the carotid body, i.e. at the bifurcation of the common carotid artery, and in the aortic bodies (Fig. 20).


 Fig. 20.  Location of the peripheral chemoreceptors. Carotid bodies are located at the bifurcation of the carotid arteries, and aortic bodies at the aortal arch. The carotid bodies are responsible for about 80% of the ventilatory effects of hypoxia. The carotid bodies are innervated by sinus nerves, branches of the glossopharyngeal (IX), and the aortic bodies are innervated by branches of the vagus (X). Activity from peripheral chemoreceptors arrives to neurons located within the dorsal respiratory groups (shaded areas).

The carotid and aortic bodies are made up of blood vessels, structural supporting tissue and numerous nerve endings of sensory neurons of the glossopharyngeal (in carotid body) and vagus nerves (in aortic bodies). The afferent fibres of these receptors project to the dorsal group of respiratory neurons in the medulla.

Ventilatory response to increased PCO2

Stimulation of central chemoreceptors increases minute ventilation and the resulting hyperventilation reduces PCO2 in the blood and therefore in the cerebrospinal fluid.

The ventilatory response to CO2 is measured by having a subject breathing different CO2 mixtures or rebreathe expired air from a bag filled with O2 so that with each expiration, the inspired PCO2 gradually increases. Fig. 21 shows the relationships between minute ventilation (panel A), respiratory frequency  (panel B), and tidal volume (panel C) and the alveolar PCO2. There are almost linear relationships between the three ventilatory variables and PCO2. The sensitivity of the respiratory controller to changes in PCO2 is remarkable. A change of 1 mmHg of arterial PCO2 (within the 40-50 range) causes a change in ventilation of about 3 L/min. These steep slopes of the relationships show that the mechanism for keeping the PaCO2 constant is a very sensitive one.

 Fig. 21.  Ventilatory response to hypercapnia (elevated CO2 in blood). Small increases in PCO2, increase minute ventilation (A) due to an increase in respiratory rate (B) and tidal volume (C).

The ventilatory response to CO2 is increased by hypoxia and depressed during sleep and anesthesia. Thus under these conditions, the slope of the PCO2 and Ve relationship of decreases.

Ventilatory response to decreased PO2

The effects of hypoxia on ventilation can be studied by having a subject breathe gas mixtures with decreased concentrations of O2. Fig. 22 illustrates the relationship between minute ventilation and alveolar PO2.

Fig. 22.  Ventilatory response to hypoxia (low PO2 in arterial blood). Minute ventilation is not significantly affected by a drop in PO2 down to 60 mmHg in alveolar gas. Further drop in PO2 causes rapid increase in VE. The VE response to hypoxia is accentuated at increased PCO2.

During normocapnia (control levels of CO2 in blood), the alveolar PO2 can be reduced to about 60 mmHg before any appreciable changes in minute ventilation occur (for comparison see %Hb02 vs PO2 relationship, Fig. 11). At increased PCO2, a decrease in PO2 below 100 mmHg can already cause an increase in minute ventilation. Hence, the combined effects of both stimuli result in a greater ventilatory excitation than each stimulus given separately. Therefore, an increase in PCO2 and a decrease in PO2 interact giving an augmented ventilatory response.

Pulmonary vagal receptors

Receptors in the lung have been divided into three major groups:

                    1. Pulmonary Slowly Adapting Stretch Receptors (SAR)

2. Pulmonary Rapidly Adapting Stretch Receptors, also called "Irritant" Receptors (RAR)

3. Juxta-capillary, called J receptors (C - fibres)

Afferent fibres from all these receptors travel in the vagus nerves. Section of vagus nerves results in a slow and deep breathing.

1. SAR are located in smooth muscles of the trachea down to the terminal bronchioles. They are innervated by large,     myelinated fibres and they discharge in response to distension of the lung. Their activity is sustained as long as the lung is distended. Fig. 23, upper trace, shows response of pulmonary stretch receptors to changes in lung volume. Some SARs are active at FRC (low threshold SARs). Other SARs are active only at volumes above FRC (high threshold SARs). Activity of these receptors phasically increases as lung volume increases during each inspiration.


Fig. 23. Activities of vagal pulmonary slowly adapting stretch receptors (SAR; A) and rapidly adapting receptors (RAR, B) during phasic changes in lung volume and during maintained lung inflation (airway occlusion at end inspiration). During normal breathing, SAR activity increases with each inspiration. At functional residual capacity FRC, expiration) activity of SAR has low frequency. When lung volume is maintained at an increased level, SAR activity is also maintained, but its frequency slowly decreases: SARs slowly adapt to the stimulus (stretch). During normal respiration, activity of RAR is irregular and scanty. It may be present at the beginning and the end of inspiration. At the beginning of airway occlusion, RAR activity is augmented but it rapidly disappears: RAR rapidly adapt to the stimulus.

The reflex effect of tonic stimulation (Fig. 23A) of these receptors is a decrease in respiratory frequency due to a prolongation of expiratory time. This effect is called the Hering-Breuer inflation reflex and can be activated by an artificially increase in FRCin ventilated subjects. This reflex is rather weak in adults, but it is strong in newborn babies. Therefore, in a newborn baby small changes in FRC may result in a decreased minute ventilation.

2. RAR are located between airway epithelial cells in the trachea down to respiratory bronchioles. They are stimulated by increase in lung volume (Fig. 23B), noxious gases, cigarette smoke, lung deflation, histamine and dust. RAR's are innervated by myelinated fibres and their stimulation leads to bronchoconstriction and hyperpnea (rapid breathing). RAR may be important in the reflex bronchoconstriction triggered by histamine release during an allergic asthmatic attack.

3. C-fibres. The name of these receptors (juxta-capillary) originates from their localization in the alveolar walls close to the capillaries. They are innervated by nonmyelinated fibres and have short lasting bursts of activity. C-fibres are stimulated by an increase in pulmonary interstitial fluid such as might occur in pulmonary congestion and edema. The reflex effects caused by these receptors include apnea (arrest of breathing) followed by rapid and shallow respiration, hypotension and bradycardia. The C-fibres may play an important role in dyspnea (sensation of difficulty in breathing) associated with left heart failure and lung edema or congestion.