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Phol 480: Pulmonary Physiology Section

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Title: Phol 480: Pulmonary Physiology Section


1
Phol 480 Pulmonary Physiology Section Session 3
Control Instructor Jeff Overholt e-mail
jxo_at_po.cwru.edu phone 8962 location E616
Medical School Text Berne and Levy, Fourth ed.
Chapter 36
Powerpoint Presentations are on Frank
Sonnichsens lab home page. Go to the Department
of Physiology and Biophysics page, go to Faculty
and click on Franks 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.
2
  • 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 PO2s
    over which hemoglobin will release O2.

3
  • Transport of CO2
  • CO2 is transported in three forms.
  • 1. Dissolved in plasma (7)
  • 2. Combined with hemoglobin (25)
  • 3. Carbonic Acid (70).

4
  • Alveolar Ventilation
  • The quantity of air moved into and out of the
    alveoli each minute
  • Alveolar Ventilation Equation
  • 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.

5
Overall view of the Control of Breathing
6
  • 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.

7
  • 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.

8
  • 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.

9
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.
10
  • 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
    off-switch for inspiration-causes sustatined
    inspiration (apneusis)
  • Probably works in conjunction with the
    pneumotaxic center to control the depth of
    inspiration.

11
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.
12
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.
13
  • Central Control (contd)
  • 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.

14
  • 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.

15
  • Carotid Bodies (contd)
  • 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.

16
  • Carotid Bodies (contd)
  • 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.

17
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 16299-308, 1973.
18
  • Carotid Bodies (contd)
  • How is O2 sensed by glomus cells?
  • One possible hypothesis
  • In glomus cells, potassium channels have been
    identified that are sensitive to O2.

19
Ca2
Ca2
K
Depolarization ()
K
Glomus Cell
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.

20
  • 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.

21
CO2/O2 Interactions (contd)
22
  • 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

23
  • 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)

24
  • 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.

25
  • 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.

26
  • 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.

27
  • 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.
28
  • 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.

29
  • Cheyne-Stokes Breathing (contd)
  • 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

30
  • 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.

31
  • Ventilation and Exercise (contd)
  • 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.

32
  • Ventilation and Exercise (contd)
  • 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.

33
Ventilation and Exercise (contd) Exercise
shifts the alveolar CO2 ventilation response
curve.
34
High Altitude and Breathing
35
(No Transcript)
36
To look at it another way The control of a
physiological system can be compared to a
physical plant system.
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