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Phol 480: Pulmonary Physiology Section
Session 3: Control
Instructor Jeff Overholt
e-mail: [email protected]
phone: 8962
location: E616 Medical School
Text: Berne and Levy, Fourth ed. Chapter
36
Powerpoint Presentations: are on Frank
Sonnichsen’s lab home page. Go to the
Department of Physiology and Biophysics page,
go to Faculty and click on Frank’s name. Then
proceed to his lab home page
(http://pout.cwru.edu/~frank/). Once on his home
page click on Course Materials, you will find the
files under PHOL 480.
Brief Review of Gas Exchange:
O2 Transport:
• One liter of plasma holds only 3 ml of O2 (at PO2 of
100 mmHg). This is not sufficient to supply the
metabolic consumption of O2,which is about 250
ml/min.
• Therefore higher organisms developed a special
molecule to aid in O2 transport in the blood:
Hemoglobin (Hb)
• Each hemoglobin molecule can bind 4 O2
molecules, and binding is cooperative. This gives
hemoglobin a sigmoidal saturation curve.
• Hb is saturated with PO2's above 60-70 mmHg (flat
upper portion of saturation curve).
• Steep part of curve reflects the range of PO2‘s over
which hemoglobin will release O2.
Transport of CO2:
•CO2 is transported in three forms.
1. Dissolved in plasma (~7%)
2. Combined with hemoglobin (~25%)
3. Carbonic Acid (~70%).
In the Lungs:
Tissues:
Alveolar Ventilation:
• The quantity of air moved into and out of the alveoli
each minute
Alveolar Ventilation Equation:
VCO 2 * K
VA 
PACO2
• Where VA is alveolar ventilation (L/min), VCO2 is the
metabolic production of CO2 and PACO2 is alveolar
PCO2 and K is a constant (0.863 mmHg x L/min).
This equation shows the intimate relationship
between alveolar CO2 and alveolar ventilation.
Control of breathing can therefore be
simplified to the fact that both the rate
and depth of breathing are regulated so
that alveolar PCO2 is maintained close
to 40 mmHg.
Overall view of the Control of Breathing:
Control of Breathing:
Breathing is unique in that it involves both
automatic (metabolic) and voluntary (behavioral)
control. Control encompasses both the rhythm
generating apparatus and the chemical and
physical factors that modulate the basic rhythm.
1) The main function of the control of breathing is
to adjust the rate of alveolar ventilation to
maintain arterial PO2 and PCO2 constant.
• The venous PO2 and PCO2 can change
considerably during periods of increased
demand/usage as in exercise.
2) How do we maintain PO2 and PCO2 levels
constant?
• The large reserve of air in the lungs (FRC)
relative to the small alveolar ventilation (350 ml)
helps to maintain gas levels constant.
In times of need, it is also necessary to increase
alveolar ventilation. Can change both the rate
and depth of breathing.
PCO2 is the parameter that is most tightly
regulated.
Rhythm Generation:
Generating the basic rhythm of respiration, the
Respiratory Center.
The rhythm generating system is not well
understood.
What we do know?
•The medulla can be separated from the rest of
the brain and the respiratory pattern stays
relatively normal.
•Respiratory control lies in the brainstem in
several groups located bilaterally in the medulla
and pons.
Overview (two main medullary groups):
1. DRG (dorsal respiratory group) lies in the dorsal
portion of the medulla in the nucleus of the tractus
solitarius (NTS).
• The NTS is also the site of integration for the sensory
inputs from the vagus and glossopharyngeal nerves.
• Primarily concerned with inspiration.
2. VRG (ventral respiratory group) lies in the
ventrolateral part of the medulla in the nucleus
retroambiguous.
• Neurons fire during both inspiration and expiration.
Not much activity during normal breathing. Increase
respiratory drive and the VRG contributes rhythmic
activity to the respiratory controller.
• Overdrive mechanism-contributes especially to the
expiratory signals to the abdominal muscles during
expiration.
DRG:
The dorsal group is the main driving force for inspiration.
-repetitive bursts of inspiratory activity.
How is rhythm generated?
One hypothesis:
There is a continuous inspiratory drive from the DRG
and an intermittent inhibitory signal that inhibits
inspiration and causes expiration.
-Reciprocal inhibition of interconnected neural
networks.
Pool A generates a continuous respiratory drive and sends
outputs to the muscles of inspiration and to the neurons
in pool B.
Pool B is stimulated by pool A and also sends inputs to the
muscles of breathing and to Pool C.
Pool C sends inhibitory inputs to pool A. The inhibitory
signals terminate inspiration.
-When the excitation reaches a critical level, pool C
switches off the inspiratory neurons in pool A causing
termination of inspiration and beginning of expiration.
Higher Centers in the Pons:
Pneumotaxic center: located dorsally in the pons.
• Influences switching between inspiration and
expiration. Controls the offswitch.
• Strong activity: short breaths, Weak activity: long
breaths
• When the pneumotaxic center is inactivated,
inspiration is prolonged (apneusis).
Apneustic Center: located in the lower part of the
pons.
• Not sure of the function. Contributes when the
vagal and pneumotaxic centers have been
severed.
• Sends signals to the DRG that prevent the offswitch for inspiration-causes sustatined
inspiration (apneusis)
• Probably works in conjunction with the
pneumotaxic center to control the depth of
inspiration.
The inspiratory signal is a ramp.
There is a steady increase in the signal that causes a
steady increase in lung volume rather than gasping like
breathing.
Can control the signal in two ways.
1. Increase the rate of rise (slope of the ramp). During
inspiration, increasing the slope of the ramp increases
the speed of filling the lungs.
2. Control the limiting point (end point) of the ramp. This
is the most common method. The longer the duration of
the ramp, more filling of the lungs.
The signals to the muscles of the upper airways are not a
ramp. This insures that the muscles of the upper
airways are active just before the inspiratory effort from
the diaphragm. Maintains patency of the upper airways
during inspiration.
Control of respiratory center activity:
Control consists of both chemical (O2, CO2, pH)
and physical factors.
A. Central:
The main stimulus to central chemosensitivity is
CO2.
-CO2 is a much more sensitive measure because
normal O2 delivery occurs over a wide range of
ventilation. (Hb is saturated well below normal
PO2 at sea level).
-There is little direct effect of O2 on the
respiratory center.
Central Control (cont’d):
• The central chemosensitive area is a separate group of
neurons located in the ventral part of the medulla. The
chemosensitive area sends inputs to the DRG.
• Very sensitive to H+ ions, however, H+ ions in blood can
not cross the blood brain barrier or blood cerebrospinal
fluid barriers.
• Changes in CO2 in the blood have a bigger effect on the
chemosensitive area because CO2 can easily cross the
blood brain and blood cerebrospinal fluid barriers.
• However, CO2 itself has very little direct effect on the
chemosensitive area.
Rather, CO2 reacts with
water to form carbonic
acid, which dissociates
into H+ and HCO3-.
Therefore, more H+ is
released into the
chemosensitive area when
blood PCO2 increases than
when blood H+ increases,
and consequently blood
PCO2 has more effect on
respiration than blood pH.
• However, the effect of CO2 is an acute effect, that is it
declines after a few hours.
-The kidneys increase HCO3- production that binds the
excess H+.
Peripheral control:
The Peripheral Chemoreceptors, mainly the carotid and
aortic bodies.
• Especially important for sensing changes in arterial O2.
(Remember, there is very little stimulatory effect of O2 in
the central chemosensitive area. Rather, in central
neurons, hypoxia (low O2) depresses breathing.
• Also sense arterial CO2 and are responsible for ~25% of
the CO2 drive to the central respiratory generator. The
peripheral chemoreceptors respond rapidly to CO2 and
are probably responsible for the immediate (first few
breaths) response to CO2.
The Carotid Bodies:
• Located bilaterally in the bifurcation of the common
carotid arteries.
• Prime location since this is the point of entry for the
oxygenated blood into the systemic circulation.
• Innervated by both afferent (sensory) and efferent nerve
fibers.
• The afferent fibers travel up the glossopharyngeal nerve
to the neurons of the DRG in the NTS.
Carotid Bodies (cont’d):
Primarily responsible for the increased respiratory
drive during hypoxia.
•Respond to hypoxia with an increase in discharge
in the carotid sinus nerve, the sensory nerve
leaving the carotid body. Very sensitive to changes
in O2 in the 30-60 mmHg range.
Carotid Bodies (cont’d):
•The carotid body is highly vascular. The blood
flow rate is 20X their weight/min. This means that
there is essentially no removal of O2 from the
blood and the carotid bodies are constantly
exposed to arterial blood.
Carotid Body Morphology:
The carotid body is composed of 2 types of cells:
1. Type I (Glomus) cells:
Neuronal origin
Believed to be chemoreceptor cells
-destruction ablates hypoxic sensory response
2. Type II cells:
Glial-like, serve a supportive role
From A. Verna, J. Microscopie 16:299-308, 1973.
Carotid Bodies (cont’d):
How is O2 sensed by glomus cells?
One possible hypothesis:
•In glomus cells, potassium channels have been
identified that are sensitive to O2.
Hypoxia
Ca2+
Ca2+
K
+
Depolarization (+)
Ca2+ 2+
Ca
K
+
Glomus
Cell
Second Messenger
Pathways
(+)
(-)
Sensory
Activity
Carotid
Sinus
Nerve
K+ Channel Hypothesis:
• K+ channels set the resting membrane potential because
they are open at that potential.
• Decreasing arterial O2 decreases K+ current, causing the
membrane to depolarize
• Depolarization causes opening of Ca2+ channels.
• Opening of Ca2+ channels increases intracellular Ca2+
causing release of neurotransmitters.
• Release of an excitatory neurotransmitter causes
excitation of the carotid sinus nerve that sends impulses
to the brainstem neurons controlling respiration.
The effects of O2 and CO2 are synergistic:
•This is a paradox, i.e. when you lower arterial PO2
and stimulate breathing via the carotid body, the
increased breathing decreases the arterial PCO2.
•The decreased PCO2 depresses the central
chemosensitive area and therefore the overall
effect of low PO2 on respiration is decreased.
•There is a much greater effect of changes in
arterial PO2 when PCO2 and H+ remain constant.
•This can occur in certain diseases that interfere
with the exchange of gases across the pulmonary
membrane, i.e., pneumonia and emphysema.
CO2/O2 Interactions (cont’d):
Overall Picture of O2 and CO2 Interactions:
•Solid line represents the effect of PCO2 on
ventilation at pH 7.4 with different PO2 values.
•Comparing these lines shows the effect of
changing PO2 on the ventilatory effect of PCO2.
•Dashed line represents the effect of PCO2 on
ventilation at pH 7.3 while varying the PO2.
•Comparing the solid lines and the dashed lines
indicates the effect of pH.
*lower PO2, greater effect of PCO2 on ventilation.
*lower pH, greater effect of PCO2 on ventilation.
*slope of the line is the sensitivity, position of
the line is the threshold
Mechanical Control of Breathing:
•Sensory receptors in the lung and airways are
stimulated by irritation of the mucosa and
changes in the distending pressure.
•Afferent (sensory) neurons travel up the vagus to
the brainstem areas controlling respiration.
Three types of pulmonary receptors:
1. Stretch receptors (regulatory)
2. Irritant receptors (protective)
3. C-fibers (protective)
Stretch Receptors:
• Stretch receptors are excited by an increase in
bronchial transmural pressure.
• Very slowly adapting
• Located in the muscular portions of the bronchi
and bronchioles
• Inhibit inspiration and promote expiration
• Afferent fibers run in the vagus to the respiratory
brainstem center in the DRG
• Hering-Breuer reflex: produces apnea in response
to large lung inflation and stimulates expiratory
muscles.
Irritant and C-Fibers:
•Located in the epithelium of the trachea, bronchi
and bronchioles.
•Cause coughing and sneezing to prevent entrance
of irritants into the gas exchange areas. Lead to
rapid shallow breathing.
•Rapidly adapting.
•Stimulated by noxious agents such as ammonia
and inhaled antigens.
Other factors affecting breathing:
•In the alert, conscious human external stimuli act
reflexly at the brain centers to affect breathing.
•Reticular activating system: modulates the
brainstem controller by affecting the state of
alertness.
•During sleep the reticular activating system is
shut down and the cerebral influences are
withdrawn.
•Ventilation decreases and arterial PCO2 increases
•There is a decrease in both threshold and
sensitivity to CO2.
•The sensitivity to O2 is maintained by the carotid
body.
Sleep Apnea:
• The activity of the upper airway muscles (nose, pharynx
and larynx) also decreases during sleep.
• The negative pressure during inspiration is normally
counterbalanced by activity of the upper airway muscles
that function to keep the upper airway open.
• Inspiration tends to collapse the upper airway due to
negative pressure. In mild cases leads to snoring.
• In extreme cases closing of the upper airways leads to
sleep apnea.
• Two types of sleep apnea.
1. Obstructive: muscles of the upper airway are
depressed during sleep more than the diaphragm.
Causes upper airway to close during inspiration.
In babies can be one form of SIDS
2. Central: cessation of all breathing, electrical activity
is absent in phrenic nerves.
Sleep apnea results
in arousal (probably
from peripheral
input from the
carotid body), which
therefore causes
very bizarre sleep
patterns.
Other Abnormal Breathing Patterns:
Cheyne-Stokes Breathing:
•Repeating cycle of breathing deeply for a short
interval followed by breathing slightly or not at
all.
•Over breathing causes an increase in PO2 and a
decrease in PCO2 in pulmonary blood. It takes
several seconds for the changed blood to reach
the chemosensitive areas in the brain. By this
time the over ventilation has lasted a few extra
seconds. When the respiratory center finally
responds it is too depressed because of the over
ventilation and the cycle starts again.
• The depth of respiration corresponds to the
PCO2 in the blood in the chemosensitive
areas in the brain, not in the pulmonary
blood.
Cheyne-Stokes Breathing (cont’d):
Two situations where it can occur.
•Long delay in transport of blood from the lungs to
the brain.
-severe cardiac failure, left side of heart is
enlarged and blood flow is slow.
•Increased negative feedback gain in the respiratory
control areas.
-hypersensitivity to changes in arterial PCO2 and
PO2
-can occur in brain damage
Ventilation and Exercise:
Changes are geared to both the intensity and
duration.
•To make up for the increased demand for O2 both
perfusion and ventilation are increased.
1. Increased recruitment of capillaries to
increase the area for gas diffusion.
2. Increased tidal volume to increase the
distension of the airways.
3. Increase the rate of breathing
4. Increase the utilization coefficient
5. Increase cardiac output
•During moderate exercise, the acid-base balance
is normal because O2 delivery to the cells is
adequate to match mitochondrial requirements.
Ventilation and Exercise (cont’d):
•During more intense exercise, cells use a
combination of aerobic and anaerobic (glycolysis)
metabolism.
1. Glycolysis releases lactic acid into the blood
and increases H+.
2. The level of work that sustains metabolic
acidosis is the anaerobic threshold.
• Below the anaerobic threshold, ventilation is
linearly related to O2 consumption and CO2
production. The arterial PO2, PCO2 and pH
remain unchanged.
Ventilation and Exercise (cont’d):
However, measurements of arterial PCO2, PO2 and
pH show that none of these changes significantly
during exercise.
So where does the stimulus for increased ventilation
come from?
•There are two possible known effects:
1. The brain, on sending signals to the contracting
muscles, also sends impulses to the central
brainstem respiratory centers.
2. Body movements (especially the arms and legs)
increase ventilation by exciting joint and muscle
proprioceptors that send impulses to the
brainstem respiratory center.
Ventilation and Exercise (cont’d):
Exercise shifts the alveolar CO2 ventilation
response curve.
High Altitude and Breathing:
To look at it another way:
The control of a physiological system can be
compared to a physical plant system.