REGULATION OF RESPIRATION AND

RESPIRATORY REFLEXES
BY
FRANK FUBARA EGBONO (PhD)
REGULATION OF RESPIRATION
Breathing is controlled by the central neuronal network to meet the metabolic demands o f the
body
– Neural regulation
– Chemical regulation
Respiratory center
Definition: –A collection of functionally similar neurons that help to regulate the respiratory
movement
Respiratory centers
Medulla and Pons
Basic respiratory center: produce and control the respiratory
Higher respiratory center
cerebral cortex rhythm, cerebral cortex, hypothalamus & limbic system
Spinal cord
motor neurons
NEURAL REGULATION OF RESPIRATION
Voluntary breathing center – Cerebral cortex Cerebral cortex
Automatic (involuntary) breathing center
–Medulla
– Pons
 CONTROL OF RESPIRATION:
Neural Generation of rhythmic breathing
Breathing depends entirely upon cyclical respiratory muscle excitation of the diaphragm and
the intercostal muscles by their motor neurons.
Inspiration is initiated by a burst of action potentials in the spinal motor neurons to inspiratory
muscles like the diaphragm. Then the action potentials cease, the inspiratory muscles relax, and
expiration occurs as the elastic lungs recoil.
In situations such as exercise when the contraction of expiratory muscles facilitates expiration,
the neurons to these muscles, which were not active during inspiration, begin firing during
expiration.
DORSAL RESPIRATORY GROUP (DRG)
Control of this neural activity resides primarily in neurons in the medulla oblongata, There are
two main anatomical components of the medullary respiratory center.
The neurons of the dorsal respiratory group (DRG) primarily fire during inspiration and have
input to the spinal motor neurons that activate respiratory muscles involved in inspiration—the
diaphragm and inspiratory intercostal muscles. The primary inspiratory muscle at rest is the
diaphragm, which is innervated by the phrenic nerves.
Inspiratory motor neurons are driven primarily by the DRG while expiratory motor neurons
(active mostly during forced expiration and strenuous exercise) are driven primarily by the
VRG.
DRG and VRG innervate each other allowing phasic inspiration and expiration.
The centers in the upper pons are primarily responsible for fine-tuning respiratory control.
VENTRAL RESPIRATORY GROUP (VRG)
The ventral respiratory group (VRG) is the other main complex of neurons in the medullary
respiratory center. The respiratory rhythm generator is located in the pre-Bötzinger complex of
neurons in the upper part of the VRG. This rhythm generator appears to be composed of
pacemaker cells and a complex neural network that, acting together, set the basal respiratory
rate.
The VRG contains expiratory neurons that appear to be most important when large increases in
ventilation are required (for example, during strenuous physical activity). During active
expiration, motor neurons activated by the expiratory output from the VRG cause the
expiratory muscles to contract.
This helps to rapidly move air out of the lungs rather than depending only on the passive
expiration that occurs during quiet breathing.
During quiet breathing, the respiratory rhythm generator activates inspiratory neurons in the
DRG that depolarize the inspiratory spinal motor neurons, causing the inspiratory muscles to
contract.
When the inspiratory motor neurons stop firing, the inspiratory muscles relax, allowing passive
expiration.
During increases in breathing, the inspiratory and expiratory motor neurons and muscles are not
activated at the same time but, rather, alternate in function.
MEDULLARY INSPIRATORY NEURONS
The medullary inspiratory neurons receive a rich synaptic input from neurons in various areas
of the pons, the part of the brainstem just above the medulla.
This input fine-tunes the output of the medullary inspiratory neurons and may help terminate
inspiration by inhibiting them. It is likely that an area of the lower pons called the apneustic
center is the major source of this output, whereas an area of the upper pons called the
pneumotaxic center modulates the activity of the apneustic center. The pneumotaxic center,
also known as the pontine respiratory group, helps to smooth the transition between inspiration
and expiration.
The respiratory nerves in the medulla and pons also receive synaptic input from higher centers
of the brain such that the pattern of respiration is controlled voluntarily during speaking,
diving, and even with emotions and pain.
HERING–BREUER REFLEX
Another cutoff signal for inspiration comes from pulmonary stretch receptors, which lie in the
airway smooth muscle layer and are activated by a large lung inflation.
Action potentials in the afferent nerve fibers from the stretch receptors travel to the brain and
inhibit the activity of the medullary inspiratory neurons. This is called the Hering–Breuer
reflex. This allows feedback from the lungs to terminate inspiration by inhibiting inspiratory
nerves in the DRG. However, this reflex is important in setting respiratory rhythm only under
conditions of very large tidal volumes, as in strenuous exercise.
The arterial chemoreceptors (next slide) also have important input to the respiratory control
centers such that the rate and depth of respiration can be increased when the levels of arterial
oxygen decrease, or when arterial carbon dioxide or H+ concentration increases.
A final point about the medullary inspiratory neurons is that they are quite sensitive to
inhibition by sedatives-hypnotics (such as barbiturates) and opiates (such as morphine, heroin,
and fentanyl). Death from an overdose of these drugs is often due directly to a cessation of
breathing.
CONTROL OF VENTILATION BY PO2, PCO2, AND H+ CONCENTRATION
Chemoreceptors
Respiratory rate and tidal volume are not fixed but can be increased or decreased over a wide
range.
There are many inputs to the medullary inspiratory neurons, but the most important for the
automatic control of ventilation at rest come from peripheral (arterial) chemoreceptors and
central chemoreceptors.
The peripheral chemoreceptors, located high in the neck at the bifurcation of the common
carotid arteries and in the thorax on the arch of the aorta) are called the carotid bodies and
aortic bodies, respectively. In both locations, they are quite close to, but distinct from, the
arterial baroreceptors and are in intimate contact with the arterial blood.
LOCATION OF THE CAROTID AND AORTIC BODIES
Each carotid body is quite close to a carotid sinus, the major arterial baroreceptor. Both right
and left common carotid bifurcations contain a carotid sinus and a carotid body. The carotid
bodies, in particular, are strategically located to monitor oxygen supply to the brain.
The peripheral chemoreceptors are composed of specialized receptor cells stimulated mainly
by a decrease in the arterial PO2 and an increase in the arterial H+ concentration
These cells communicate synaptically with neuron terminals from which afferent nerve fibers
pass to the brainstem. There they provide excitatory synaptic input to the medullary
inspiratory neurons.
The carotid body input is the predominant peripheral chemoreceptor involved in the control
of respiration.
CENTRAL CHEMORECEPTORS
The central chemoreceptors are located in the medulla and, like the peripheral
chemoreceptors, provide excitatory synaptic input to the medullary inspiratory neurons. They
are stimulated by an increase in the H+ concentration of the brain’s extracellular fluid. Such
changes result mainly from changes in blood PCO2.
CONTROL BY PO2
Little increase in ventilation is observed until the oxygen concentration of the inspired air is
reduced enough to lower arterial PO2 to 60 mmHg. Beyond this point, any further decrease in
arterial PO2 causes a marked reflex increase in ventilation.
This reflex is mediated by the peripheral chemoreceptors. The low arterial PO2 increases the rate
at which the receptors discharge, resulting in an increased number of action potentials traveling
up the afferent nerve fibers and stimulating the medullary inspiratory neurons.
The resulting increase in ventilation provides more oxygen to the alveoli and minimizes the
decrease in alveolar and arterial PO2 produced by the low- PO2 gas mixture.
Total oxygen transport by the blood is not really decreased very much until the arterial PO2
decreases below about 60 mmHg. Therefore, increased ventilation would not result in much more
oxygen being added to the blood until that point is reached.
To reiterate, the peripheral chemoreceptors respond to decreases in arterial PO2 , as occurs in
lung disease or exposure to high altitude. However, the peripheral chemoreceptors are not
stimulated in situations in which modest reductions take place in the oxygen content of the blood
but no change occurs in arterial PO2 .
CONTROL BY PCO
Anemia is a decrease in the amount of hemoglobin present in the blood without a decrease in
arterial PO2 , because the concentration of dissolved oxygen in the arterial blood is normal
Some pulmonary diseases, such as emphysema, can cause the body to retain carbon dioxide,
resulting in an increase in arterial PCO2 that stimulates ventilation. This promotes the
elimination of the carbon dioxide. Conversely, if arterial PCO2 decreases below normal levels
for whatever reason, this removes some of the stimulus for ventilation. This decreases
ventilation and allows metabolically produced carbon dioxide to accumulate, thereby returning
the PCO2 to normal. In this manner, the arterial PCO2 is stabilized near the normal value of 40
mmHg.
PATHWAYS BY WHICH INCREASED ARTERIAL PCO2 STIMULATES
VENTILATION.
The ability of changes in arterial PCO2 , to reflexively control ventilation is largely due to
associated changes in H+ concentration
Both the peripheral and central chemoreceptors initiate the pathways that mediate these
reflexes. The peripheral chemoreceptors are stimulated by the increased arterial H+
concentration resulting from the increased PCO2 , . At the same time, because carbon dioxide
diffuses rapidly across the membranes separating capillary blood and brain interstitial fluid,
the increase in arterial PCO2 , causes a rapid increase in brain extracellular fluid PCO2 , .
This increased PCO2 , increases brain extracellular fluid H+ concentration, which stimulates
the central chemoreceptors.
Inputs from both the peripheral and central chemoreceptors stimulate the medullary inspiratory
neurons to increase ventilation. The end result is a return of arterial and brain extracellular
fluid PCO2 , and H+ concentration toward normal.
Of the two sets of receptors involved in this reflex response to increases in PCO2, the
central chemoreceptors are the more important, accounting for about 70% of the
increased ventilation.
The effects of increased PCO2 , an decreased PO2 , not only exist as independent inputs to the
medulla but potentiate each other’s effects. The acute ventilatory response to combined low
PO2 , and high PCO2 , is considerably greater than the sum of the individual responses.
Very high levels of carbon dioxide actually inhibit ventilation and may be lethal. This is
because such concentrations of carbon dioxide act directly on the medulla to inhibit the
respiratory neurons by an anesthesia-like effect. Other symptoms caused by very high blood
PCO2 , include severe headaches, restlessness, and dulling or loss of consciousness.
Control by Changes in Arterial H+ Concentration That Are Not Due to Changes in
Carbon Dioxide
It is established that Retention or excessive elimination of carbon dioxide causes respiratory
acidosis and respiratory alkalosis, respectively. There are, however, many normal and
pathological situations in which a change in arterial H+ concentration is due to some cause
other than a primary change in PCO2. This is termed metabolic acidosis when H+
concentration is increased and metabolic alkalosis when it is decreased.
In such cases, the peripheral chemoreceptors provide the major afferent inputs to the brain in
altering ventilation. For example, the addition of lactic acid to the blood, as in strenuous
exercise, causes hyperventilation almost entirely by stimulation of the peripheral
chemoreceptors.
The central chemoreceptors are only minimally stimulated in this case because brain H+
concentration is increased to only a small extent, at least early on, by the H+ generated from
the lactic acid.
This is because H+ penetrates the blood– brain barrier very slowly. In contrast, as described
earlier, carbon dioxide penetrates the blood– brain barrier easily and changes brain H+
concentration.
EFFECT OF H+ IONS ON RESPIRATION
The converse of the previous situation is also true: When arterial H+ concentration is
decreased by any means other than by a reduction in PCO2 , (for example, by the loss of H+
from the stomach when vomiting), ventilation is reflexively depressed because of decreased
peripheral chemoreceptor output. The increased ventilation induced by a metabolic acidosis
reduces arterial PCO2 , , which decreases arterial H+ concentration back toward normal.
Similarly, hypoventilation induced by a metabolic alkalosis results in an increase in arterial
PCO2 , and consequently a restoration of H+ concentration toward normal.
When a change in arterial H+ concentration due to some acid unrelated to carbon dioxide
influences ventilation via the peripheral chemoreceptors, PCO2 , is displaced from normal.
This is a reflex that regulates arterial H+ concentration at the expense of changes in arterial
PCO2 , . Maintenance of normal arterial H+ is necessary because nearly all enzymes of the
body function best at physiological pH. Reflexively induced hyperventilation minimizes the
change in arterial H+ concentration when acids are produced in excess in the body. Note that
under such conditions, arterial PCO2 is reflexively reduced below its normal value. E
Summary of the major chemical inputs that stimulate ventilation. When arterial PO2 ,
increases or when PCO2 , or H+ concentration decreases, ventilation is reflexively
decreased.
CONTROL OF VENTILATION DURING EXCERSISEDuring exercise, the alveolar
ventilation may increase as much as 20-fold.
On the basis of our three variables—PO2, PCO2 and H+ concentration—it may seem easy to
explain the mechanism that induces this increased ventilation.
This is not the case, however, and the major stimuli to ventilation during exercise, at least
moderate exercise, remain unclear.
Increased PCO2 as the Stimulus
It would seem logical that, as the exercising muscles produce more carbon dioxide, blood
PCO2 would increase. This is true, however, only for systemic venous blood but not for
systemic arterial blood.
Why is it that arterialPCO2 does not increase during exercise? There are two factors from the
section on alveolar gas pressures: (1) Arterial PCO2 is determined by alveolar PCO2 , and (2)
Alveolar PCO2 is determined by the ratio of carbon dioxide production to alveolar ventilation.
During moderate exercise, the alveolar ventilation increases in exact proportion to the increased
carbon dioxide production, so alveolar and therefore arterial PCO2 do not change. In fact, in
very strenuous exercise, the alveolar ventilation increases relatively more than carbon dioxide
production.
In other words, during strenuous exercise, a person may hyperventilate; thus, alveolar and
systemic arterial PCO2 may actually decrease alveolar and therefore arterial PCO2 do no
change.

The effect of exercise on ventilation, arterial gas pressures, and H+ concentration. All these
variables remain constant during moderate exercise; any change occurs only during strenuous
exercise, when the person is actually hyperventilating (decrease in PCO2 ).
Decreased PO2 as the Stimulus
The story is similar for oxygen. Although systemic venous PO2 decreases during exercise due
to an increase in oxygen consumption in the tissues, alveolar PO2 and, therefore, systemic
arterial PO2 usually remain unchanged
This is because cellular oxygen consumption and alveolar ventilation increase in exact
proportion to each other, at least during moderate exercise.
In healthy individuals, ventilation is not the limiting factor in strenuous exercise—cardiac
output is. Ventilation can increase enough to maintain arterial PO2 .
Increased H + Concentration as the Stimulus?
Because the arterial PO2 does not change during moderate exercise and decreases during
strenuous exercise, there is no accumulation of excess H+ resulting from carbon dioxide
accumulation.
However, during strenuous exercise, there is an increase in arterial H+ concentration due to the
generation and release of lactic acid into the blood. This change in H+ concentration is
responsible, in part, for stimulating the hyperventilation accompanying strenuous exercise.
OTHER FACTORS
A variety of other factors are involved in stimulating ventilation during exercise. These include
(1) Reflex input from mechanoreceptors in joints and muscles, (2) An increase in body
temperature, (3) Inputs to the respiratory neurons via branches from axons descending from the
brain to motor neurons supplying the exercising muscles (central command), (4) An increase in
the plasma epinephrine concentration, (5) An increase in the plasma K+ concentration due to
movement of K+ out of the exercising muscles, and (6) A conditioned (learned) response
mediated by neural input to the respiratory centers.

VENTILATION CHANGES DURING EXERCISE

Factors (1) and (3) (from previous slide) are most likely to be significant. There is an abrupt
increase— within seconds—in ventilation at the onset of exercise and an equally abrupt
decrease at the end; these changes occur too rapidly to be explained by alteration of chemical
constituents of the blood or by altered body temperature.
SUMMARY OF FACTORS THAT STIMULATE VENTILATION DURING EXERCISE

Voluntary Control of Breathing

It is accomplished by descending pathways from the cerebral cortex to the motor neurons of the
respiratory muscles.
This voluntary control of respiration cannot be maintained when the involuntary stimuli, such
as an increased PCO2 or H+ concentration, become intense. An example is the inability to hold
breath for very long.
The opposite of breath holding—deliberate hyperventilation— lowers alveolar and arterial
PCO2 and increases PO2 . Swimmers sometimes voluntarily hyperventilate immediately before
underwater swimming to be able to hold their breath longer. But sometimes low PCO2 may still
permit breath holding at a time when the exertion is decreasing the arterial PO2 to levels that
can cause unconsciousness and lead to drowning.
Besides the obvious forms of voluntary control, respiration must also be controlled during such
complex actions as speaking, singing, and swallowing
REFLEXES FROM J RECEPTORS
In the lungs, either in the capillary walls or the interstitium, are a group of sensory receptors
called J receptors. They are normally dormant but are stimulated by an increase in lung
interstitial pressure caused by the collection of fluid in the interstitium.
Such an increase occurs during the vascular congestion caused by either occlusion of a
pulmonary vessel (called a pulmonary embolism) or left ventricular heart failure, as well as by
strenuous exercise in healthy people.
The main reflex effects are rapid breathing (tachypnea) and a dry cough. In addition, neural
input from J receptors gives rise to sensations of pressure in the chest and dyspnea—the feeling
that breathing is labored or difficult.
INVOLUNTARY CONTROL
Involuntary respiration is under subconscious control. The diaphragm and intercostal
muscles are the primary respiratory muscles. They are stimulated by groups of neurons located
in the pons and medulla. These neurons form the respiratory control centre. They send
impulses to the primary respiratory muscles, via the phrenic and intercostal nerves, which
stimulate their contraction. There are three main groups of neurons involved in respiration:
•The ventral respiratory group controls expiration
•The dorsal respiratory group controls inspiration
•The pontine respiratory group controls the rate and pattern of breathing
Once the neurons stop firing, the inspiratory muscles relax and expiration occurs.
VOLUNTARY CONTROL
Voluntary respiration is under conscious control. It is controlled via the motor
cortex in the cerebrum, which receives inputs from the limbic
system and hypothalamus. The mechanisms involved aren’t completely
understood, but signals are thought to be sent to the spinal cord from the
motor cortex, which are then passed onto the respiratory muscles.

Regions of the brain, neurons in the motor cortex are responsible for voluntary control
PHRENIC NERVE PARALYSIS
Phrenic nerve paralysis is where damage to the phrenic nerve results in its dysfunction. This can
cause paralysis of the diaphragm, therefore causing breathing problems. Patients may lose the
ability to regulate their own breathing.
Common causes include: spinal cord injury, neck injury and surgical complications.