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 P_aO₂ around 70 mmHg and P_aCO₂ 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 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 P_aO₂ is too low (less than 60 mmHg) or P_aCO₂ is higher than 40 mmHg.  Activity of the respiratory neurons will decrease if P_aO₂ is higher than 100 mHg or P_aCO₂ 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).
 

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).
 

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.

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 P_aCO₂ constant is a very sensitive one.
 
 

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.

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.
 

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.

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

                    1. Pulmonary Slowly Adapting Stretch Receptors (SAR)

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.