Introduction –

Oxygen must be supplied continuously as the body does not have much store oxygen The
amount present in the lungs blood and tissues is only about 1200 ml which is just enough for
resting requirements of five minutes O2 deprivation causes loss of consciousness within 20 sec.
and irreversible brain damage in about 4 minutes CO2 also cannot be stored as it is toxic and
causes adverse effects
Regulation of respiration provides the means by which pulmonary ventilation is adjusted
in accordance with the changing metabolic demands of the body . The magnitude of the
respiratory of the body movements is altered from time to time to meet the following basic need.
 Supply of adequate O2 proportional to the degree of bodily activity.
 Removal of CO2 formed during metabolism and
 Maintenance of optimum pH of blood (In animals which do not have sweat glands e.g.
dogs respiration has as important role in regulating body temperature).
The rate depth and rhythm of respiration are governed by a group of neurons situated in the
reticular formation of the brain stem This is collection of nerve cells which controls
respiratory activity is referred to as the Respiratory Center. The activity of the Venter is
modified by the chemical composition of its fluid environment as well as by nervous
influences.
The “Respiratory center” is composed of several widely dispersed group of neurons
located bilaterally in the medulla oblongata and pons, it is divided into three major
collections of neurons a dorsa respiratory group located in the dorsal portion of the medulla
which mainly causes inspiration a ventral respiratory group located in the ventrolateral part
of the medulla which can cause either expiration or inspiration depending upon which
neurons in the group are stimulated and the pneumotaxic center located dorsally in the
superior portion of the pons which helps control both the rate and pattern of breathing The
dorsal respiratory group of neurons plays the fundamental role in the control of respiration.
Concept of Respiratory Center–
The respiratory venters are located in the medulla and pons and are made up of the
following groups and are responsible for automatic rhythmic breathing.

1. Medullary Respiratory Center – They comprise two groups a dorsal and a ventral
situated in the reticular formation of the medulla extending along it length Electrical
stimulation of the dorsal group produces only inspiratory effects while on stimulating the
ventral group some neurons evoke expiratory responses while others cause inspiratory
effects These indicate that the dorsal group is entirely inspiratory but the ventral group is
both expiratory and inspiratory.
a) Dorsal Respiratory Group – DRG is situated mainly in the ventrolateral part of
the nucleus of the Tractus solitarius (NTS) It contains only inpiratory (I) neurons
It sends fibres to the following structures.
i. Motor output promarilyto the contralateral phrenic motor neurons which
innervate the diaphragm.
ii. I neurons of the ventral respiratory group.
iii. Pneumotaxic center
The afferent fibres of the vagus and glossopharyngeal nerves end in the NTS and thus the
dorsal group receives peripheral afferent fibres which influence respiration.
b) Ventral Respoiratory Group – (VRG) contains boths inspiratory (I) and
expiratory (E) neurons It is situated lateral to the DRG and is made up of two sub
groups.
i. A Cranial or rostral portion in relation to the nucleus ambiguous (NA)
which innervates the ipsilateral laryngeal muscles (abductors and
adductors) via the vagus nerves.
ii. Acaudal portion in relation to the nucleus retroambiguus (NRA) which
connects with the motor neurons of the intercostal and abdominal muscles
and a few also to the diaphragm of both sides The rostral part of the
ventral group (NA) contains mainly I neurons while the caudal part (NRA)
contains mainly E neurons the VRG does not appear to receive peripheral
respiratory afferents
 The mudullary inspiratory (I) neurons discharge impulses during inspiration The
expiratory (E) neurons are inactive during quiet breathing but discharge impulses during forced
breathing rhythmic discharge of impulses arises only in the I neurons of DRG The I neurons of
the VRG do not have the ability of spontaneous generation of impulses they are driven by the I
neurons of the DRG .

2. Pontine Center – There are two groups in the pons.

a) Pneumotaxic Center (PNC) is situated in the dorsolateral part of the upper pons in
the nucleus parabrachialis (NPB) and the Kolliker Fuse nucleus It contains both I
and E neurons Electrical stimulation of PNC causes respiration to prematurely
switch from one phase to the other The meurons of the PNC do not generate
impulses from the I neurons of the DRG causing inhibitory impulses to be sent to
medullary I neurons Hence PNC is normally inhibitory to the medullary
inspiratory centers.

“CHAMICAL CONTROL OF RESPIRATION”

The basic mechanisms for causing inspiration and expiration but it is also important to
know how the intensity of the respiratory control signals is increased or decreased to match the
ventilatory needs of the body For example during very heavy exercise the rates of oxygen
utilization and carbon dioxide formation are often increased to as much as 20 time normal
requiring commensurate increases in pulmonary ventilation
The ultimate goal of respiration is to maintain proper concentration of oxygen carbon
dioxide and hydrogen ions in the tissues It is fortunate there fore that respiratory activity is
highly responsive to changes in each of these.
Excess carbon dioxide of hydrogen ions mainly stimulate the respiratory center it self
causing greatly invreased strength of both the inspiratory and expiratory signals to the respiratory
muscles.
Oxygen on the other hand does not have a significant direct effect on the respiratory
center of the brain in controlling respiration Instead It acts almost entirely on peripheral
chemoreceptor’s located in the carotid and aortic bodies and these in turn transmit appropriate
nervous signals to the respiratory center for control of respiration.
 The stimulation of the respiratory center itself by carbon dioxide and hydrogen ions.
Chemical Control of Respiration –
Chemical Control ofrespiration (or Ventilation) is achieved by the following factors.
• Centre factors - CO2 and H+ in CSF
• Peripheral factor - Inputs from carotid and aortic body receptors which respond to
changes in arterial pH, PCO2 and PO2
The single most important factor controlling ventilation is the PaCO2 acting in the central
chemoreceptors. The CO2 dominated chemical control of respiration maintains a verntilation
sufficient for adequate tissue ocygeneration CO2 removal from tissues and maintenance of
optimal pH.
Central chemoreceptors
These are chemosensitives cells concentrated in two major areas at the ventral surface of
the medlla
The two areas are :
a) A rostral area (RA, near the roots of CN VI, VII, VIII, IX and X).
b) A caudal area (CA, near the base of the CN XII).

Diagram - 1

There is an intermediate area (IA) between the two which most probably integrate the
activity of chemoreceptor’s in RA and CA Efferent’s from these receptors pass to the contra
lateral brainstem. They have a major projection to the DRG neurons. There is a nucleus called
paragigantocellular nucleus adjacent to the chemoreceptor areas. This nucleus appears to
mediate chemo sensitivity.
The central chemoreceptor’s are bathed in CSF and they are stimulated by H+ in CSF.

Mechanism of central chemo sensitivity

H+ concentration is CSF bathing ventral medulla modulates afferent impulse from
ventral chemoreceptor CSF (H+) is determined by arterial PCO2 and acidosis small changes in
extra cellular pH of ventral medulla cause marked change in tidal volume pH CO2 is hydrated to
form H2CO3 which then dissociates to produce H+ and HCO3– H+ enters tissues and stimulates
chemoreceptor’s to increase ventilation.

Irritant Receptor Reflexes

These are mediated by rapidly adapting receptors (RARs) located in the tracheal
epithelium especially in the carinal region. These RARs are stimulated by mechanical or
chemical endogenous irritation of the epithelium Various pollutants as well as endogenious
compounds like histamine and brady kinin can also stimulate the irritant receptors Responses
include coughing sneezing, tachypnes (increased respiratory rate), bronchovonstriction and
invreased secretion in the airways.

j- Receptors Reflexes.
j-receptors are pulmonary juxtacapillary mechanoreceptors sending afferent impulse
through unmyelinated C fibres These receptors in the alveolar interstitum sense vascular
distension and invreases in interstitial fluid volume. Their stimulation causes hyperpnea with of
without dyspnea when there is pulmonary vascular congestion and edema j receptor activity in
response to elevated left atrial pressure is illustrated.

Adaptoation of Central Chemoreceptors

The ventilatory response to changes in PaCO2 is rapid but it tends to wane with time (hours
to days). This is due to passage of HCO3- across the blood brain barrier, there by burrering the H+
of the medullary ECF. Movement of HCO3- occurs from plasma to CSF during chronic
hypercapnia HCO3 moves in the opposite direction during chronic hypocapnia.
Ventilatory Response to CO2 and H+
Changes in PaCO2 invreases alveolar ventilation Decrease in arterial pH due to metabolic
acidoses also stimulates ventilation but the response is lesser than that produced by an invrease
in paCO2.

Daigran 2

Mechanism of Peripheral Chemoreceptor’s –

When action potentials are recorded from the afferent nerves of the chemoreceptors
impulse discharge is observed even when breathing room air. The frequency of impulse traffic is
increased when the inspired CO2 is raised (alveolar PCO2 above 40 mm Hg) ir O2 content is
reduced (alveolar PO2 below 100 mm Hg) The impulse traffic decreases with a fall in PCO2 and
rise in PO2 and is suppressed with O2 rich mixture or when alveolar PCO2 is about 30 mm Hg
These obervations suggest a possible role of chemoreceptor’s even during normal breathing On
the other hand when the ventilatory responses to changing CO2 and O2 concentrations are
examined somewhat different results.
Carbon dioxide sine central chemoreceptor stimulation is more powerful and dominant
and the ventilatory responses to CO2 excess can be maintained even after sinoaortic denervation
it is apparent that for normal breathing as well as for hyperventilation of CO2 excess peripheral
chemoreceptor’s are not necessary But they are useful for producing rapid responses during
sudden changes in CO2 they also modify the peripheral chemoreceptor response to hypoxia.
Oxygen -
1. Breathing oxygen rich mixtures does not produce singifecant change in ventilation (any
fall is only small and transient and a more sustained change is a slight rise in ventilation)
2. O2 lack must be fairly large (alveolar PO2 below 60 mm Hg) to produce an increase in
ventilation. These observations suggest that hypoxic chemoreceptor drive is of little
 importance in eupneic breathing (The possible reasons for the smaller effects of hypoxin
on ventilation have been discussed eaerlier)
It must however be remembered that hypoxia directly depresses the respiratory center but
normally the chemoreceptor effects over come the depressant effect on the center and
increase respiration Unlike many other cells the chemoreceptors are not easily damaged by
severe O2 lack and are resistant to adverse conditions. It has been shown that
chemoreceptors discharge impulses for about 30 minutes after death due to circulatory and
respiratory failure The chemoreceptors may be regarded as the ultimum moriens of the
respiration regulating system and but for the chemoreceptors the organism would rapiedly
succumb to hypoxia. And constitute the first line of defence against hypoxia.

Stimulation of Chemoreceptors byDevreased Arterial Oxygen.

Changes in arterial oxygen concentration have no direct stimulatory effect on the
respiratory center itself but when the oxygen concentration in the arterial blood falls below
normal the chemoreceptors become strongly stimulated which shows the effect of different
levels of arterial PO2 rate of nerve impulse transmission from a carotid body Note that the
impulse rate is particularly sensitive to changes in arterial Po2 in the range between 60 and
30 mm Hg the range in which the arterial hemoglobin saturation with oxygen decreases
rapidly. Effect of Carbon Dioxide and Hydrogen Ion Concentration on Chemoreceptor
Activity An increase in either carbon dioxide concentration or hydrogen ion concentration
also excites the chemoreceptors and in this way indirectly increases respiratory activity
However the direct effects of both these factors in the respiratory center itself are so much
more powerful than their effects mediated through the chemoreceptors (about seven times as
power full) that for most practical purposes the indirect effects through the chemoreceptors
do not need to be considered.
Corbon dioxide
When the inspired air CO2 concentration is increased to 2% pulmonary ventilation is
slightly invreased and is doubled when CO2 concentration is 4 % More marked and
progressive invrease in ventilation occurs beyond concentration of 5 % reaching values 8 to
10 time resting levels at 10% CO2 However toxic symptoms appear as CO2 concentration
exceeds 7% and leads to loss of consciousness depression and cessation of respiration
beyond 15% CO2 concentration.
When inspired CO2 concentration is high the alveolar PCO2 is invreased and less CO2
deffuses from pulmonary capillaries into the alveoli raising the arteral PCO2 This stimulates
respiration invreases pulmonary ventilation and washes out more CO2 from the alveoli
restoring alveolar and arterial PCO2 to normal however when inspired CO2 is very high
above 7% the alveolar PCO2 is increased to levels close to and even higher than venous
PCO2 and so in spite of vonsiderable over ventilation CO2 elimination is inadequate and
toxic symptoms appear.
A reduction in alveolar PCO2 inhibits respiration The diminished pulmonary ventilation
results in retention of CO2 which restores alveolar and arterial PCO2 Thus the ventilatory
response to CO2 is a very important mechanism which serves to maintain arterial PCO2
within very narrow normal limits at about 40 mm Hg.
H ion concentration Increase in H ion concentration (acidaemia) stimulates respiration
and increases both the rate and depth of breathing A decrease in H ion concentration
(alkalaemia) depresses breathing and reduces pulmonary ventilation. The H ions act mainly
on the peripheral chemoreceptor’s of the carotid body. They act on the central
chemoreceptor’s when the H concentration of the blood is high and H+ is able to cross the
barrier H+ can also act directly on the respiratory centre .

Oxygen Transport –
Oxygen (O2) is transported in blood mainly in combination with hemoglobin in RBCs
Dissolved O2 in plasma is onlya fraction (0.3 ml/100 ml of blood at a PO2 of 100 mm Hg) of
the total O2 carried by blood but this form is significant because O2 has to get dissolved in
plasma to pass to and from hemoglobin (Hb).
Hb is a chromoprotein with four polypeptide chains one mole of Hb can combine
with upto 4 moles of O2 Theoretically 1 g. of Hb can combie with 1.39 of O2 However since
a small fraction of Hb stays in an inactive form the actual of O2 that combines with 1 g of Hb
is somewhat lesser than 1.38 ml.
The binding of O2 to Fe2+ of Hb is referred to as oxygenation (instead of oxidation) does
not change after this combination. Oxygenation of Hb gives rise to oxyhemoglobin (HbO2)
which is bright red in color Deoxygenated Hb.(Hb) is purple in color Oxidation of Hb results
in conversion of Fe2+ to Fe3+ producing methemoglobin which cannot release its O2 to
tissues.
Oxygen content of blood at any particular moment is the volume of O2 combined with
Hb plus the volume of O2 in solution The maximum volume of O2 that can be bound by Hb
is known as O2 capacity of Hb The O2 saturation of Hb (SO2) is expressed in terms of
percentage of the O2 capacity In a healthy adult breathing room air at sea level the partial
pressure of O2 in arteral blood (PaO2) is 100 mmHg and SaO2 is approximately 97.5% the
arteral O2 content (CaO2) being 20 ml/100 ml of blood in mixed venous blood of a healthy
adult in similar condition PVo2, Svo2 and Cvo2 are 40 mm Hg,70% and 15 ml/100ml of
blood respectively This give an arteriovenous difference in O2 content of (20-15) = 5 ml /100
ml of blood this amount of O2 is therefore consumed by the tissue concerned A blood is flow
(Q) of 5000 ml/min will thus ensure an O2 consumption (VO2) of 250 ml per minute by that
tissue.