6/24/2022

Introduction

 Respiration is regulated by a complex integration of neural control

mechanisms which are modified by certain respiratory reflexes and
Regulation of Respiration chemical control mechanisms.

 Neural control mechanisms include:

 A system for automatic control of respiration as an involuntary

function. This is located in the medullary and pontine centres of the
Dr. Khaleel Ahmed Manik brainstem.
Prof and HOD
 A system for voluntary control of respiration is located in the
cerebral cortex.

Respiratory centre

Sensors
 Involuntary control which allows human to breathe without conscious
efforts under all circumstances including sleep and is thus essential for life.  Chemoreceptors and other receptors (e.g. stretch, irritant, chest wall
and J-receptors)
 The voluntary control system facilitates acts like talking, singing,
swimming, breath holding and voluntary hyperventilation. Central controllers

 Respiratory reflexes which modify the effects of neural mechanisms are

those initiated by stimulation of stretch receptors, irritant receptors, J-
receptors and chest wall receptors.
 Chemical control mechanisms are influenced by alterations in arterial
pO2, pCO2 and H+ concentration.
 Medullary, pontine and other parts of the brain, adjust the efferent
outputs as per the body needs and convey to the effectors.
Effectors
 Respiratory muscles which perform their activity as per the neural
discharges received.

1
 6/24/2022

 Functions of respiratory regulatory mechanisms include:

 Genesis of normal respiratory spontaneous rhythm. This is the function

of medullary and pontine centres of neural mechanism.

 Control of rate and depth of respiration i.e. adjustment of total ventilation

to match metabolic needs of the body so that arterial oxygen tension (pO2),
carbon dioxide tension (pCO2 ) and H+ concentration (pH) are almost
maintained constant, for e.g, during exercise.

 This function is accomplished by all the respiratory control mechanisms

acting in unison.

NEURAL REGULATION OF RESPIRATION

To make it easier to understand this regulation is studied under

1. Neural regulation of respiration

2. Chemical regulation of respiration

2
 6/24/2022

NEURAL REGULATION OF RESPIRATION

AUTOMATIC CONTROL SYSTEM

Neural regulation of respiration
NEURAL GENESIS OF RESPIRATORY RHYTHM

The neural mechanisms regulating respiration can be described under two

headings:
 The involuntary neual control system regulates respiration by several
 Automatic control system groups of neurons situated bilaterally in medulla and pons,
 Afferent impulses to respiratory centres.
 They include medullary respiratory centres, pontine respiratory centres
and reticular activating system (RAS).

Respiratory centre
Centers
1. Dorsal Respiratory Group (DRG)
• Located bilaterally in
medulla oblongata and pons. 2. Ventral Respiratory Group (VRG)
Function
Generate the basic respiratory rhythm
Generate the basic respiratory rhythm

• Composed of 3. Pneumotaxic center (PNC) Modify activity of medullary centres

1. Dorsal Respiratory Group
(DRG) 4. Apneustic center (APN) Modify activity of medullary centres

2. Ventral Respiratory Group

(VRG)

3. Pneumotaxic center

4. Apneustic center

Centers Function MEDULLARY RESPIRATORY CENTRES

1. Dorsal Respiratory Group (DRG) Causes inspiration

(consists of Nucleus Tract Solitarius)  The medullary respiratory centres include two groups of neurons: the

Role in both inspiration and expiration but

DRG and VRG, which generate the basic respiratory rhythm.
2. Ventral Respiratory Group (VRG) maily becomes active in forceful expiration
 A group of neurons called pacemaker cells form the pre-Botzinger
Fine tuning of respiration, inhibit inspiration complex, which is situated between nucleus ambiguus and lateral
3. Pneumotaxic center (PNC) and allow transition from inspiration to
expiration
reticular nucleus.

4. Apneustic center (APN) Controlling inspiration  The rhythmic activity is initiated by these synaptically coupled
( consists of parabrachial nucleus)
neurons.

 These neurons discharge rhythmically and generate rhythmic motor

. Apneusis – prolonged inspiration
activity in phrenic nerve, hypoglossal nerve and intercostal nerves.

3
 6/24/2022

Dorsal respiratory group neurons

 Most of the neurons are located within the nucleus of tractus solitarius (NTS) Dorsal Respiratory Group (DRG) Ventral Respiratory Group (VRG)
and some in the adjacent reticular substance.
1. I neurons 1. Pre botzinger complex

 The neurons of DRG are of three types: 2. IOS Neurons 2. Botzinger complex

 Inspiratory neurons 3. Integrator neurons 3. Nucleus ambiguus rostrally

4. Nucleus retroambigus caudally

 Inspiratory off-switch (IOS) neurons

 Integrator neurons

Inspiratory neurons Inspiratory neurons

I-neurons discharge during inspiration only. Axons of I-neurons cross the midline and
descend on the contralateral side of spinal cord
Make contact with the spinal motor neurons of the inspiratory muscles, namely the
diaphragm & external intercostal muscles
In other words, the DRG neurons are the upper motor neurons of respiratory muscles.
 The DRG mainly contains I-neurons that discharge during inspiration only.
 The axons of I-neurons cross the midline and descend on the contralateral side of
spinal cord to make contact with the spinal motor neurons of the inspiratory muscles,
namely the diaphragm (supplied by the phrenic nerve arising from C3 to C5) and the
external intercostal muscles (supplied by the intercostal nerves). In other words, the
neurons in the DRG are the upper motor neurons of respiratory muscles.

Produce a ramp signal, i.e. it is weak in the beginning and it steadily increases in a ramp
manner for about 2s and is thus called inspiratory ramp.
This leads to a steady increase in the lung volume during inspiration rather than the
respiratory gasps (abrupt distension).
Ramp signal then abruptly ceases for approximately next 3s.
 From I-neurons, nerve signals pass to the muscles of inspiration. The signal is not
instantaneous but is a ramp signal, i.e. it is weak in the beginning and it steadily
increases in a ramp manner for about 2 s and is thus called inspiratory ramp.
 This leads to a steady increase in the lung volume during inspiration rather than the
respiratory gasps (abrupt distension). Ramp signal then abruptly ceases for
approximately next 3s.

• Fibers from DRG reach the motor

neurons in spinal cord between C3
& C5 to form phrenic nerve

• Complete lesion of spinal cord

above C3 will stop the breathing

• Lesion after C5 will not affect the

respiration

4
 6/24/2022

Inspiratory off-switch (IOS) neurons.

• Ramp signals controlled  Inspiratory off- switch neurons refer to a group of neurons that are
by
responsible for terminating the activity of I-neurons & causes turning off of
(a) Pneumotaxic center
(b) Stretch receptors in the excitation of muscles of inspiration.
lungs
Significance of ramp signals  These muscles, therefore relax allowing elastic recoil of the chest wall and
• No gasping the lungs to cause expiration.
• Smooth inflation of lungs
 After expiration again there is signal for starting another cycle.
Full cycle of respiration
5 seconds Integrator neurons.
• 2sec inspiration
• 3 sec expiration  Integrator neurons are present near the I-neurons and are stimulated by them.

 They subserve following integrating functions:

 The integrator neurons when depolarize to a critical level lead to firing of

the so-called IOS neurons which are responsible for terminating the
inspiratory ramp.

 The I-neurons trigger the IOS neurons indirectly through integrators and
thereby bring about the termination of their own discharge.

 This forms the basic circuity of an automatic respiratory rhythm. In this

way, cycle of inspiration/expiration goes on continuously to cause tidal
respiration.

 The integrator neurons receive both excitatory and inhibitory inputs and
thus integrate the activity of I-neurons and IOS neurons accordingly.

Excitatory inputs to integrator Inhibitory inputs to integrator

neurons neurons

1. Cerebral cortex 1. Medullary inhibitory neurons

2. Pneumotaxic centre 2. Apneustic centre

3. Vagal afferents from stretch

receptors

5
 6/24/2022

Role of VRG neurons

 The VRG neurons normally remain totally inactive during quiet

Dorsal Respiratory Group (DRG) Ventral Respiratory Group (VRG)
breathing.
1. I neurons 1. Pre botzinger complex
 The VRG neurons become active during inspiration (role of I-neurons) as 2. IOS Neurons 2. Botzinger complex
well as expiration (role of E-neurons) during forceful respiration.
3. Integrator neurons 3. Nucleus ambiguus rostrally

 This area is especially important in providing powerful expiratory 4. Nucleus retroambigus caudally
signals to expiratory muscles.

 Thus, VRG operates when high levels of pulmonary ventilation is

required, for example, during exercise.

Ventral Respiratory Group (VRG) Function

1. Pre botzinger complex Pacemaker for respiration

2. Botzinger complex Controls expiration

3. Nucleus ambiguus Role in inspiration by controlling

soft palate, some pharynx and
larynx muscles.

4. Nucleus retroambigus Has both inspiratory and expiratory

control

Pre botzinger complex(Pacemaker for respiration) - Through special leaky

cat ion channels – spontaneous depolarise – action potential development – to
inspiratory muscles

PONTINE RESPIRATORY CENTRES

The pontine centres include the apneustic centre (APN) and pneumotaxic centre
(PNC), both of which modify the activity of medullary respiratory centres.

Apneustic centre

 Apneustic centre refers to a group of inhibitory neurons located bilaterally

in the lower part of pons.

 It sends signals to the integrator neurons of DRG that affect the IOS
neurons and prevent the switch-off of the inspiratory ramp signals from the
central inspiratory neurons.

 This increases the tidal volume and duration of inspiration, resulting in a

deeper and more prolonged inspiratory effort termed as apneusis.

6
 6/24/2022

 However, normally the apneustic centre is inhibited by impulses carried by

the vagus nerves and also by the activity of the pneumotaxic centre.

 Either of these two influences, pneumotaxic centre or the vagii, seems to be

adequate to keep apneusis in check.

 The existence and functions of APN are based on following experimental

observations:

Level – 1

 Sectioning of brain between the medulla and pons (level - 1) leaves the
basic rhythm intact indicating thereby that medullary respiratory centres
are working normally.

Level - 2

 Sectioning the brain between PNC and APN, (level - 2) along with bilateral
vagotomy leads to prolonged periods of inspiration, i.e. apneusis.

 This indicates that removal of two inhibitor influences (PNC and vagii) on
the APN allows APN to exert its influence on the medullary centres
producing apneusis.

Level - 3

 Sectioning the brain rostral to the pons (level - 3) leaves the respiratory
rhythm intact even if combined with bilateral vagotomy.

 This indicates that mere presence of check by pneumotaxic centre is

sufficient to control the apneustic effect of APN on the medullary centres.

Pneumotaxic centre

 The pneumotaxic centres are located bilaterally in the upper pons.

 Functions.

 As described above, the PNC inhibits the APN. Therefore, stimulation of

PNC shortens inspiration, leading to shallow and more rapid
respiratory pattern.

 Thus, though rhythm of respiration resides in the DRG neurons in medulla,

PNC and APN control these neurons to regulate the depth and rate of
respiration.

 So it does fine tuning of respiration, inhibit inspiration and allow transition

from inspiration to expiration.

7
 6/24/2022

AFFERENT IMPULSES TO RESPIRATORY CENTRES

 The respiratory centres generate the respiratory rhythm and execute their
effects through the efferent nerves supplying the respiratory muscles.

 The activity of respiratory centres in turn is influenced by the afferent

impulses from the lungs and various other parts of the body.

 Various afferent impulses to the respiratory centres can be grouped as

 Afferent impulses from higher centres

 Afferent impulses from nonchemical receptors, which may constitute

non-chemical regulation of respiration.

 Afferent impulses from chemical receptors, which constitute ‘chemical

regulation of respiration’ & hence has been described separately.

AFFERENT IMPULSES FROM NON-CHEMICAL RECEPTORS

 Afferent impulses from the receptors other than the chemoreceptors, i.e. from
nonchemical receptors include the following

1. Afferent impulses from pulmonary stretch receptors (Hering–Breuer reflex)

2. Afferent impulses from J-receptors

3. Afferent impulses from the irritant receptors in the respiratory tract

4. Afferent impulses from proprioceptors

5. Afferent impulses from chest wall stretch receptors

6. Afferent impulses from baroreceptors

7. Afferent impulses from thermoreceptors

Receptors Location
Receptors Location
1. Stretch receptors Bronchi & bronchioles
1. Stretch receptors Bronchi & bronchioles
2. J receptors In interstitium between capillary
2. J receptors In interstitium between capillary endothelium and alveolar epithelium
endothelium and alveolar epithelium
3. Irritant receptors Submucosa of respiratory tract
3. Irritant receptors Submucosa of respiratory tract 4. Proprioceptors In the muscles, tendons and joints

4. Proprioceptors In the muscles, tendons and joints

5. Chest wall stretch receptors Nothing but the muscle spindles
present in the intercostal muscles.
5. Chest wall stretch receptors Nothing but the muscle spindles
present in the intercostal muscles. 6. Baroreceptors (pressure receptors) Located in carotid sinus & aortic arch

7. Thermoreceptors Everywhere in body

6. Baroreceptors (pressure receptors) Located in carotid sinus & aortic arch
8. Peripheral chemoreceptors
7. Thermoreceptors Everywhere in body
9. Central chemoreceptors

8
 6/24/2022

Afferent impulses from pulmonary stretch receptors (Hering–Breuer reflex)

 Hering–Breuer reflex is a negative feedback reflex.

 In 1868, Hering and Breuer found that lung inflation inhibits output of the phrenic
motor neurons, thereby protecting lung from overinflation.

 The Hering–Breuer inspiratory inhibitory reflex is initiated when the stretch

receptors located in the smooth muscles of the bronchi and bronchioles are
stimulated by inflation of the lungs.

 The afferents of Hering–Breuer reflex are carried through vagii to the

pontomedullary respiratory centres to inhibit respiration.

 This reflex has an important role in controlling TV during eupnoea in human

infants.

Afferent impulses from J-receptors

 In adults this reflex is weakest, therefore, it does not play any regulatory role
 Afferent impulses from J-receptors constitute the J-reflex.
in tidal respiration.

 The J-receptors were discovered by an Indian physiologist A. S. Paintal in 1954.

 The reflex is initiated only when the tidal volume is more than 1–1.5 L, thus, the
reflex tends to limit the tidal volume.  The name J-receptors (juxtapulmonary capillary receptors) was given to them
because of their location very close to the pulmonary capillaries.

 Important features of J-receptors are:

 J-receptors are basically unmyelinated vagal afferent nerve endings (type C fibres).

 These receptors are primarily sensitive to increase in the content of interstitial fluid
between the capillary endothelium and alveolar epithelium, therefore they are stimulated
in conditions like pulmonary congestion, pulmonary oedema, pneumonia,
hyperinflation of lungs and microembolism in pulmonary capillaries.

 The J-reflex response is characterized by apnoea followed by tachypnoea

(rapid and shallow breathing), bradycardia, hypotension and weakness of
skeletal muscles.

 Physiological role of J-receptors has been postulated during exercise

especially at high altitude when some fluid is entrapped in the alveolar
interstitial space which stimulates the J-receptors producing dyspnoea and
reduction of the skeletal muscle tone.

 This effect would discourage exercise, thereby taking away the trigger for
pulmonary congestion.

9
 6/24/2022

Afferent impulses from irritant receptors in the respiratory tract

 Irritant receptors are located below the mucosa of whole respiratory tract.

 These are stimulated by a variety of chemical stimuli.

 These agents include serotonin, prostaglandins, bradykinin, ammonia,

smoke, noxious gases, particulate matter in the inspired air and in a number
of other conditions.

 An important function of these receptors may be to detect pathophysiological

processes in the airway, such as chemical irritation, inflammation,
congestion, etc.

 These receptors also detect histamine which produces bronchoconstriction in

asthma. These receptors initiate following reflexes:

 These receptors initiate following reflexes:

Cough reflex.
1. Cough reflex
 This is a protective reflex caused by stimulation of irritant receptors in the
2. Sneezing reflex pharynx, larynx, trachea and bronchi (conducting zone of respiratory tract).

3. Hering–Breuer deflation reflex  Cough begins with a deep inspiration followed by a forced expiration with
closed glottis. So, intrapleural pressure rises above 100 mm Hg.
4. Deglutition reflex
 The glottis is then suddenly opened producing an explosive outflow of air.

 The velocity of the air flow may reach 960 km/h.

 By this endeavour the irritants may be expelled out of the respiratory tract.

Hering–Breuer deflation reflex

 It is produced on stimulation of irritant receptors located in the bronchial

Sneezing reflex epithelium due to distortion of bronchial epithelium caused by large deflations
of the lungs as seen in pneumothorax and lung collapses (atelectasis).
 It is also a protective reflex produced on stimulation of irritant receptors
of the nasal mucosa.  This reflex may also be responsible for the sighs or yawning.

 Role : The reflex helps in opening up the collapsed alveoli again.

 The sneezing begins with deep inspiration followed by forceful expiration
with opened glottis (in cough reflex where glottis is closed).

Deglutition reflex

 It refers to a temporary apnoea produced during pharyngeal phase of

swallowing of food.

 Role : It is a protective reflex which prevents the entry of food particles into the
respiratory tract.

10
 6/24/2022

Afferent impulses from chest wall stretch receptors

IMPORTANT NOTE
Afferent impulses from proprioceptors  Chest wall stretch receptors are nothing but the muscle spindles present in the
intercostal muscles.
 Proprioceptors are the receptors present in the muscles, tendons and joints and
are stimulated during change in the position of different parts of the body.  Stretching of the intercostal muscles produce a stretch reflex due to the
stimulation of muscle spindles that is characterized by contraction of
 Role
intercostal muscles.
 This reflex helps in increasing ventilation during exercise.
 Role
 The paediatricians employ this reflex for initiating first breath in the
 The muscle spindles present in the respiratory muscles help to coordinate
newborn by slapping it.
breathing during change in posture or during speech.

 They play a special role in maintaining normal tidal volume when

breathing is impeded by an increase in airway resistance or a decrease in
pulmonary compliance.

Afferent impulses from baroreceptors

 When the mechanical load on the respiratory system is increased,
 Baroreceptors or pressure receptors located in the carotid sinus and aortic arch
intercostal muscles are stretched and their muscle spindles are
are stimulated by an increase in the arterial blood pressure.
stimulated leading to increased strength of contraction of the intercostal
muscles.  Though they play a primary role in regulation of blood pressure, but the impulses
do travel to respiratory centres and cause inhibition of respiration
 It has been observed that increase in the intercostal nerve afferent
activity leads to contraction of neighbouring intercostal muscles.  Role

 In physiological conditions the baroreceptors play an insignificant role in

regulation of respiration.

 The adrenaline apnoea observed on injection of high doses of adrenaline

causes a large rise in the arterial pressure which in turn inhibits respiration by
afferent impulses from the baroreceptors to the respiratory centres.

Afferent impulses from thermoreceptors

 Thermoreceptors are those receptors which are stimulated by a change in the

body temperature. CHEMORECEPTORS
 When warm receptors are stimulated, the impulses are conveyed to cerebral
cortex via somatic afferent nerves.

 Cerebral cortex in turn stimulates the respiratory centres to produce

hyperventilation.

 Role

 Respiration helps to maintain body temperature, as some amount of heat is

lost in the expired air.

 In dogs, panting is one of the major mechanisms of thermoregulation.

11
 6/24/2022

Peripheral chemoreceptors Central chemoreceptors

CHEMICAL REGULATION OF RESPIRATION  Location. include the carotid and  Are the neurons that lie just beneath the
aortic bodies ventral surface of the medulla
 The chemical factors regulating respiration are pCO2, pO2 and pH of blood.
 They regulate the respiration from  The central chemoreceptors regulate the
 These factors influence respiration in such a way that their own blood levels are
breath to breath, their stimulation respiration from minute-to-minute.
maintained constant.
increases rate and depth of respiration.
 They are not stimulated by hypoxia,
 The chemical mechanism of regulation operates through the chemoreceptors.
 They are the only sites that detect rather like any other cell, they are
changes in pO2, so they are mainly depressed by hypoxia, they are mainly
 Chemoreceptors are the sensory nerve endings, which are highly sensitive to
stimulated by hypoxia stimulated by decreased CO2
changes in pCO2, pO2 and pH of blood. These are of three types:

 About 15-20% of resting respiratory  about 80–85% of the resting

 Peripheral chemoreceptors
drive is due to the stimulatory effect of respiratory drive is due to the
 Central chemoreceptors CO2 on the peripheral stimulatory effect of CO2 on the central
chemoreceptors. chemoreceptors.

PERIPHERAL CHEMORECEPTORS
Peripheral chemoreceptors Central chemoreceptors

 Location. Peripheral chemoreceptors include the carotid and aortic bodies

 Carotid body is located on either side near bifurcation of common carotid artery.

 Aortic bodies, two or more in number, are located near the arch of aorta.

 Structure. Each carotid and aortic body consists of:

 Capsule

 Sinusoidal large capillaries

 Epithelial cells

• Type I

• Type II

12
 6/24/2022

Nerve fibres
 Type I or glomus cells.
 Outside the capsule of each body, the nerve fibres acquire myelin sheath,
 Have dens core granules containing catecholamines (dopamine).
they are 2-5 μm in diameter & conduct at a rate of 7-12 m/s.

 Unmyelinated nerve endings are closely applied to these cells; these

 Afferent fibres from the carotid body join the glossopharyngeal (IX) nerve
nerve endings are cup shaped and have dopamine receptors (D2) on
and ultimately ascends to the medulla.
them.
 Those from the aortic body join the aortic nerve branch of vagus (Xth
 When exposed to hypoxia, the type 1 cells release catecholamine which
cranial) nerve and ascend to the medulla.
stimulates the D2 receptors.
Blood flow
 Type II cells, which are probably glial cells, are also closely applied to the
type 1 cells.  To each carotid and aortic body is highest in the body (2000 mL/100
g/min).

Functions.

 The peripheral chemoreceptors respond to lowered pO2, increased pCO2 and

Mechanism of chemoreceptors stimulation by hypoxia and oxygen
increased H+ concentration in the arterial blood.
transduction in glomus cells.
 The afferent impulses from the chemoreceptors stimulate the DRG neurons, which
 The peripheral chemoreceptors are stimulated by the release of neurotransmitter
lead to an increased rate and depth of respiration called hyperventilation.
by the glomus cells.
 Salient points of their functions are:
 Oxygen transduction is the process by which changes in the arterial pO2 results in
 The peripheral chemoreceptors are the only sites that detect changes in pO2. proportionate changes in the frequency of action potential discharge. The
sequence of events is:
 Carotid bodies are seven times more effective than the aortic bodies in
stimulating respiration.

 Carotid bodies increase both rate and depth of respiration, while the aortic
bodies increase only the frequency of respiration with small increase in the
ventilation.

Hypoxia leads to inhibition of K+ channels present in cellmembrane of glomus

cells leading to decrease in the K+ efflux depending upon level of pO2.

Thus, the glomus cells get depolarized in proportion to the fall in arterial pO2.

Depolarization of the glomus cells opens up the L-type Ca2+ channels in the
glomus cell membrane leading to an increase in the Ca2+ influx.

The Ca2+ influx triggers the release of neurotransmitter which stimulates the
afferent nerve endings.

13
 6/24/2022

1. O2 tension versus O2 content.

Factors affecting peripheral chemoreceptors stimulation
 The peripheral chemoreceptors monitor the dissolved O2, i.e. pO2, rather than its
1. O2 tension versus O2 content. total content.

2. Elevated pCO2  They are stimulated when pO2 falls below 60 mm Hg. Therefore, they respond to
various types of hypoxia differently as:
3. H+ concentration
 Hypoxic hypoxia in which arterial pO2 is reduced stimulates peripheral
4. Increase in plasma K+ levels chemoreceptors.

5. Asphyxia  Anaemic hypoxia, methaemoglobinaemia, or carbon monoxide poisoning do

not stimulate the peripheral chemoreceptors, because in these conditions,
though the total content of O2 may be low, but the O2 tension, which is
determined by the amount of dissolved O2 remains normal.

 Histotoxic hypoxia in which there is reduced utilization of O2 by the

tissue cells including glomus cells also stimulates chemoreceptors.

 Vascular stasis, in which the amount of O2 delivered to receptors per unit

of time is decreased leads to chemoreceptor stimulation.

2. Elevated pCO2. Elevated pCO2 (by 10 mm Hg) also stimulates the peripheral
chemoreceptors, but the major effect of CO2 is on the central chemoreceptors.

3. H+ concentration when increased in the blood (decreased pH by 0.1 unit)

stimulates the peripheral chemoreceptors.

14
 6/24/2022

4. Increase in plasma K+ levels may stimulate the peripheral chemoreceptors even

Effects of stimulation of peripheral chemoreceptors
in the absence of hypoxia. Increase in plasma K+ levels during exercise
contributes to exercise induced hyperventilation.
 They regulate the respiration from breath to breath and their stimulation
increases the rate and depth of respiration.
5. Asphyxia, i.e. combination of O2 lack plus CO2 excess in the blood stimulates the
peripheral chemoreceptors .  They also cause an increase in the blood pressure and tachycardia.

 About 15-20% of resting respiratory drive is due to the stimulatory effect

of CO2 on the peripheral chemoreceptors.

CENTRAL CHEMORECEPTORS

Location. Central chemoreceptors are the cells (neurons) that lie just beneath the
ventral surface of the medulla oblongata & are therefore also called medullary
receptors.

Innervation. The neurons forming central chemoreceptors project directly over to

the respiratory centres which are located slightly deeper to the central
chemoreceptors.

Stimulation characteristics of central chemoreceptors are:

 They respond to H+ concentration in the surrounding interstitial fluid and

cerebrospinal fluid (CSF).

 The magnitude of stimulation is directly proportional to the local H+

concentration, which in turn parallels arterial pCO2.

Mechanism by which an increase in CO2 concentration affects central

chemoreceptors.

 CO2 readily crosses blood brain barrier, because it is very soluble & uncharged. In
CSF, CO2 combines with H2O to form H2CO3 which dissociates into H+ & HCO3- .

 The increase in H+ concentration of CSF and interstitial fluid stimulates the central
chemoreceptors, whereas a decrease in the H+ concentration inhibits respiration.

 It is important to note that the blood brain barrier does not allow the charged ions (e.g.
H+, HCO3- etc.) to cross through readily.

 Because of this reason if the arterial pCO2 is kept constant experimentally a decrease in
the arterial pH (raised H+ concentration) fails to stimulate central chemoreceptors.

 Central chemoreceptors are not stimulated by hypoxia, rather they get depressed.

 Central chemoreceptors are also inhibited by anaesthesia, cyanide and during sleep.

15
 6/24/2022

Effects of stimulation of central chemoreceptors are:

 The central chemoreceptors regulate the respiration from minute-to-minute.

 Their stimulation leads to an increase in rate and depth of respiration

 It is important to note that about 80–85% of the resting respiratory drive is due
to the stimulatory effect of CO2 on the central chemoreceptors.

 While peripheral chemoreceptors provide only 15-20% of initial drive to

increase respiration.

16
 6/24/2022

EFFECT OF pO2, pCO2 AND H+ CONCENTRATION ON

RESPIRATION

At pO2 levels from 100 to 60 mm Hg, pulmonary ventilation does not increase
EFFECT OF HYPOXIA ON RESPIRATION significantly because of following reasons:

 The normal arterial pO2 is 100 mm Hg, which may fall in many conditions
producing the so called hypoxic hypoxia.
 A decrease in arterial pO2 is the most potent stimulus for the peripheral
chemoreceptors, consequently the rate of discharge in the peripheral chemoreceptors
begins to increase.
When the arterial pO2 levels falls to between 100 and 60 mm Hg, not much effect
is produced on ventilation.
 However, a marked increase in the pulmonary ventilation occurs when the pO2
falls below 60 mm Hg.
1. Breaking effect of CO2
2. Due to deoxyhaemoglobin
1. Breaking effect of CO2. When decrease in pO2 of the arterial blood stimulates
ventilation, increased ventilation causes washing out of CO2.
 This leads to decrease in pCO2 of blood which inhibits the respiration through
its effect on the central chemoreceptors.
 It opposes and neutralizes the effect of decreased pO2 & thus there is no marked
effect on ventilation. This phenomenon is called breaking effect of CO2

2. Due to hypoxia, the amount of deoxyhaemoglobin is increased which is a weaker

acid as compared to oxyhaemoglobin.

 This results in mild decrease in H+ concentration of blood which tends to

nullify the hypoxic drive on pulmonary ventilation.

 Hypoxia stimulating respiration through peripheral chemoreceptors can be

proved experimentally by denervating them.

 Under such circumstances, hypoxia cannot increase pulmonary ventilation,

rather it causes direct depression of the respiratory centre

17
 6/24/2022

EFFECT OF HYPERCAPNIA ON RESPIRATION

 Normal arterial pCO2 is 40 mm Hg, which is kept constant by chemical

regulation of respiration.

 Hypercapnia, i.e. rise in pCO2 rarely occurs due to an increase in CO2

production. Clinically, it may occur in restrictive lung disorders.

 An increase in arterial pCO2 causes a prompt increase in the pulmonary

ventilation resulting in CO2 washout and a near restoration of arterial pCO2 to
normal level (40 mm Hg).

 There exists a linear relation between increase in arterial pCO2 and increase in
pulmonary ventilation.

CO2 increases pulmonary ventilation mainly by stimulating the central

chemoreceptors.

 This can be demonstrated experimentally by removing peripheral

chemoreceptors & then making the person to breath from a bag of air with
different concentration of CO2.

 The same effect is obtained as above

CO2 is capable of increasing the pulmonary ventilation by stimulating

the peripheral chemoreceptors as well.

 When central chemoreceptors are depressed by anaesthesia, then CO2

increases respiration through stimulation of peripheral chemoreceptors.

CO2 acts as a main regulator of respiration because of following facts:

 It has a direct effect on respiratory centre through the central

chemoreceptors.

 It can cross the blood brain or blood–CSF barrier easily, therefore CO2
concentration in the CSF and in the interstitial fluid of brain increases soon
after the increase in concentration of CO2 in the blood.

 CO2 has a very strong breaking effect on the action of either decreased pO2
or pH,

 pO2 or pH does not have a very strong breaking effect on the action of
increased CO2 on ventilation

18
 6/24/2022

Carbon dioxide narcosis.

 It develops when arterial pCO2 increases above 50 mmHg. APPLIED ASPECTS

 Accumulation of such a large amount of CO2 (hypercapnia) in the body depresses the
Whenever CO2 is to be used to stimulate respiration in a comatosed patient with
CNS, including respiratory centres producing headache, confusion, convulsions and
finally coma and death may occur. respiratory depression it is always advisable to estimate the CO2 content of the

blood to avoid occurrence of death from carbon dioxide narcosis.

 Causes.

 Carbon dioxide narcosis may occur in patients with prolonged severe emphysema
or due to accidental inhalation of CO2 (in breweries, refrigeration plants, etc).

 Experimentally, it can be produced by making the person to inhale the air

containing more than 7% CO2.

 When the inspired air pCO2 approaches close to the alveolar pCO2, as a result
elimination of CO2 becomes difficult which causes alveolar and arterial pCO2 to rise
abruptly in spite of the hyperventilation.

EFFECT OF ARTERIAL pH ON RESPIRATION

 Increased H+ concentration (metabolic acidosis).

 Renal failure (when kidney fails to excrete their normal quota of H+).
 It produces prolonged respiratory centre stimulation via peripheral
 Due to accumulation of lactic acid in severe muscular exercise.
chemoreceptors, leading to a decrease in the arterial pCO2 by elimination of larger
amounts of CO2 producing compensatory fall in the blood H+ concentration.  Ketoacidosis in starvation.

 The related aspects of renal correction of acid base balance are discussed in renal  Infantile diarrhoea associated with loss of NaHCO3.
system.

 Causes of metabolic acidosis, i.e. decrease in HCO3- concentration in blood

secondary to increase in H+ concentration of blood are:

 Diabetic ketoacidosis. Hyperventilation occurring in this condition is called

Kussmaul breathing.

 Decreased H+ concentration (metabolic alkalosis)

Respiratory acidosis and alkalosis. It may be added here that primary changes in
 Depresses respiratory centre via peripheral chemoreceptors, leading to retention
the pulmonary ventilation also affect the pH of blood causing respiratory acidosis
of CO2 and an increase in the arterial pCO2.
or alkalosis.

 The secondary changes in the arterial pCO2 compensate for the primary metabolic
 Primary pulmonary hypoventilation may lead to elevation of arterial pCO2
defects and help to restore H+ concentration of blood.
(hypercapnia) producing the so called respiratory acidosis.

 Common causes of metabolic alkalosis, i.e. increase in HCO3- concentration in  Primary pulmonary hyperventilation may cause a decrease in the arterial
blood secondary to decreased H+ concentration in blood: excessive vomiting with
pCO2 producing the so called respiratory alkalosis.
loss of HCl from the body.

19