Transcript Explicit Constructivism: a missing link in ineffective

Manuscript: Explicit Constructivism: a missing
link in ineffective lectures?
Author: E.S.Prakash
Supplement 2: Constructivist Lecture
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Chemical and neural regulation of
respiration (a block of 3 lectures)
E.S.Prakash, School of Medicine, AIMST University,
Malaysia E-mail: [email protected]
How much do we already know?
Just write the answers with the question number on a sheet of paper
1.
2.
3.
4.
5.
At sea level, barometric pressure is:
mmHg
Barometric pressure is the same as atmospheric
pressure. T/F
In the upright position, ventilation-perfusion ratio is
highest in the upper lung zones. T/F
The maximum volume of air that you can expel
after a maximal inspiration is called:
The amount of air that remains in the lungs after a
tidal expiration is called:
3
Objective: We want to know how
respiration is regulated



Learning strategy: Go from known to unknown
We breathe in and out throughout our life …
Why do we have to breathe?




We need oxygen
We need to eliminate CO2
Why do we need oxygen?
Why do we need to eliminate CO2?
4

Why do we need oxygen all the time?

To power oxidative metabolism; we know, the energy
yield of oxidative metabolism is much higher
compared to anerobic metabolism

Why do we need to eliminate CO2 all the time?




CO2 is the end product of oxidative metabolism;
it is an acid;
if it accumulates in blood and body fluids, the pH of body
fluids will drop;
and we know the importance of maintaining pH of body
fluids
5
So, logically, the system that regulates
breathing should do the following:

1.
It MUST sense oxygen concentration in blood;
2.
It COULD sense oxygen concentration in cells;
3.
It MUST sense pH of blood and body fluids;
4.
It MUST be able to initiate appropriate responses so
that the above parameters are maintained within
acceptable limits.
6
The receptors that sense blood chemistry:

We will call the receptors that sense blood
chemistry – “chemoreceptors”

Where do you want to have them?

Arterial system

Or venous system

Why do you want them there?

On the arterial side of the circulation so that the
system could verify the oxygen concentration and
pH of blood that will be supplied to all tissues.
7
Indeed, chemoreceptors that sense the oxygen content
of blood are located in the aortic bodies and carotid
bodies, on the arterial side of the circulation.
http://www.medicine.mcgill.ca/physio/resp-web/Figures/Figtt20.jpg
8
Now we want to know how these chemoreceptors work:

Presumably, these cells have oxygen sensors much like
oxygen electrodes that we use to measure PO2 of a blood
sample.

Presumably, they have pH sensors, much like those that
we use in the lab to measure pH of a blood sample.

Second, they should transmit this information to
regulatory centers in the brain (which could initiate
appropriate responses)
9

From lessons in school, we recall that respiration
is regulated by centers in the medulla.
Arterial chemoreceptors SENSE…
They transmit this information to medulla
Respiratory center in medulla initiates
appropriate responses
10
Sensory innervation of arterial chemoreceptors:
http://www.medicine.mcgill.ca/physio/resp-web/Figures/Figtt20.jpg
Aortic
bodies
Sensory branches
of X cranial n.
Carotid
bodies
Sensory branch of
IX cranial n.
11
When do you think the chemoreceptors will
be called into play?







When arterial PO2 is low?
When arterial PO2 is high?
When arterial PCO2 increases?
When arterial PCO2 decreases?
When arterial pH falls?
When arterial pH rises?
All of the above?
12
So what are the normal values of each?
Parameter
Arterial pH
Normal range
7.35–7.45
Arterial PO2 (PaO2)
81–100 mm Hg
Arterial PCO2 (or PaCO2)
35–45 mm Hg
13
What “should” the response to low arterial PO2 be?




Increase in breathing rate?
Decrease in breathing rate?
Increase in depth of respiration?
Decrease in depth of respiration?

How would an increase in rate and depth of
respiration be a useful response to low PaO2?

Increase in minute ventilation is likely to increase
PaO2 toward normal – Yes / No
14
And what should the response to a rise in PaCO2 be?




Increase in breathing rate
Decrease in breathing rate
Increase in depth of respiration
Decrease in depth of respiration

How would an increase in rate and depth of
respiration be a homeostatic response to high PaCO2?

Increase in minute ventilation is likely to decrease
PaCO2 toward normal – Yes / No
15
Now, some facts about arterial chemoreceptors:


Glomus cells in carotid bodies contain oxygen
sensitive K+ channels;
They have a very high blood flow



2000 ml/100 g tissue/min;
In contrast, cerebral blood flow is 50 ml/100 g/min;
So it is 40 times greater than cerebral blood flow
16
What do high blood flows to the carotid
bodies mean?

Do you think this might allow carotid body cells to meet their
oxygen demands by consuming only oxygen dissolved in
blood?

Is it possible that they sense the amount of oxygen dissolved
in blood rather than the amount of oxygen bound to
hemoglobin?

We know they are stimulated when PaO2 is low.

If our reasoning is correct, carotid bodies would not be
stimulated in anemia where [Hb] and total oxygen content in
blood is low, but PaO2 is normal. Yes / No
17
But how important are the carotid bodies for
sensing arterial PO2?






Can you suggest an animal experiment to test this
question?
Experiment: Remove both carotid bodies
Have the animal breathe O2 poor gas
Does it hyperventilate as we would expect?
Observation: The ventilatory response to hypoxia is
virtually abolished by removal of carotid bodies.
Conclusion: The ventilation stimulating effect of
hypoxia depends largely on the carotid bodies
18
How important are the carotid bodies for
sensing arterial pH?







Can you suggest an animal experiment to test this question?
Experiment: Remove both carotid bodies.
Inject acid (say lactic acid) intravenously.
Now the pH of arterial blood will drop.
Does the animal hyperventilate as we would expect?
Observation: The ventilatory response to a drop in arterial pH
is virtually abolished by removal of carotid bodies.
Conclusion: The ventilation stimulating effect of acidosis
depends largely on the carotid bodies.
19
We said that a rise in PaCO2 would increase minute
ventilation. How is this response mediated? Is this mediated
by the carotid bodies?

1.
2.
3.


Can you suggest an animal experiment to test this
question?
Remove both carotid bodies.
Have the animal breathe a CO2 rich gas mixture.
Hold the oxygen percentage of gas mixture normal
(i.e. 21%) so that the animal is not hypoxic.
The PaCO2 will rise
Does the animal hyperventilate in response to the
rise in PaCO2?
20
Continued..

Hyperventilation in response to hypercapnia (rise
in PaCO2) occurs despite removal of carotid
bodies.

Conclusion: The increase in minute ventilation in
response to hypercapnia must be mediated by
receptors located elsewhere!
21
Now where are these receptors located?

They were localized to ventral aspect of the medulla;
Hence called medullary chemoreceptors

Link to Figure – Medullary Chemoreceptors

Sometimes called “central chemoreceptors” in contrast
to the carotid & aortic bodies (“peripheral
chemoreceptors”)

22
How do medullary chemoreceptors sense
PaCO2?
Tissue metabolism
CO2 (end product of oxidative metabolism)
PCO2 in cells and arterial blood rises
How are chemoreceptors activated?
23
A rise in PaCO2 lowers CSF pH which
is sensed by medullary chemoreceptors
CO2 crosses the blood brain barrier (BBB)
CO2
blood
brain ISF
CO2 + H2O
H2CO3
H+ + HCO3
Carbonic
anhydrase
Drop in CSF pH
24
Problem: The same mechanism can work in the
carotid bodies also; but we must explain why
central chemoreceptors are more effectively
stimulated by a rise in PaCO2 compared to
peripheral chemoreceptors







Think about it!
Clue: Does a rise in PaCO2 lower pH of blood?
Yes / No
Does a rise in PaCO2 lower pH in brain ISF? Yes
Why this difference?
CO2 is buffered in arterial blood;
What buffers CO2 in blood?
25
Continued >>

CO2 is buffered mainly by:




CSF has no hemoglobin and hardly any protein!
What is the protein concentration of plasma?


6000–8000 mg/dL
What is the protein concentration in CSF?


hemoglobin
plasma proteins
20 mg/dL
CSF has 300-400 times less protein (buffering
capacity) compared to plasma
26
So, is the presence of low concentration of
proteins in CSF ‘advantageous’? Yes / No

Yes. Otherwise, a rise in PaCO2 will not lead to a
drop in CSF pH and ventilation will not be
stimulated.
27
Is there any evidence to support the
hypothesis that a low concentration of protein
in CSF is advantageous?






Take bacterial meningitis for example;
The blood brain barrier is inflamed and leaky
Proteins in blood leak into brain ISF
CSF protein levels rise
Eventually respiratory drive is blunted. Why…
Eventually, death may occur due to accumulation of CO2
(respiratory acidosis)
28
Summary:
Chemoreceptor
Major Function
Systemic arterial
chemoreceptors (peripheral
chemoreceptors; carotid and
aortic bodies)
Essential for the ventilatory
response to hypoxia and a
drop in blood pH (acidosis)
Medullary chemoreceptors
(central chemoreceptors)
Mediate the ventilatory
response to a rise in PaCO2
29
Part Two..
Continuing from where we left off..
What is the stimulus that
normally drives spontaneous breathing?








Is it a rise in PaCO2?
Or is it a fall in PaO2?
How would you test this question?
Experiment: hold your breath for one full minute.
What happens to PaCO2 during this time?
What happens to PaO2 during this time?
How long were you able to hold your breath?
50 seconds? 1 minute? 70 seconds?
31







Why are you able to hold your breath only for a
limited time?
Breaking point: the point at which voluntary
control of breathing is overridden.
Why is breath holding broken?
Is it because PaCO2 rises enough to stimulate
breathing?
Or is it because PaO2 falls enough to stimulate
breathing?
Or is it due to a combination of both factors?
And how would you test it?
32
Continued..

IF the breaking point is due to a combination of
hypoxia and hypercapnia,

THEN, breath holding time will be greater if you
hold your breath in full inspiration (compared to
full expiration). Yes / No?

ALSO, breath holding time should be greater
when you hold your breath after breathing in
100% oxygen for some time. Yes / No?
33
You can do it and see:

Breath holding time is longer if you hold your
breath in full inspiration (compared to full
expiration) [True / false]

Breath holding time is longer after breathing in a
O2 rich gas mixture. [True / false]
34
We still have this question:
what is the stimulus that normally drives breathing?







Suggest a different simple experiment..
Hyperventilate for a minute
What happens to breathing thereafter?
There is a period of apnea…
Why this apnea?
CO2 (the stimulus for breathing) has been washed out
Conclusion: The rise in PaCO2 is probably the most
important stimulus for breathing under normal conditions.
35
Other conclusions from these experiments
regarding control of breathing:

We can control our breathing (but only to a certain
extent) – Voluntary control.
What remains to be learnt:
what is the neural basis for this?

Otherwise, for the most part, breathing is a
spontaneous (automatic) rhythm
What remains to be learnt:
what is the neural basis for this?
36
Neural mechanism of voluntary control of breathing
Note: it bypasses the respiratory center in medulla
Cerebral cortex (the “will” originates here)
(upper motor neurons)
Medulla
Spinal cord
+/-
NB: There are both
excitatory as well as
inhibitory controls
from cerebral cortex
Phrenic n.
Intercostal n.
Diaphragm
Intercostal n.
External intercostals
Muscles of expiration:
Internal intercostals
37
How do you expect
spontaneous breathing to be achieved?
1.
Spontaneous breathing must be paced by some mechanism;
there must be a pacemaker for initiating breathing like the
SA node initiates the impulse that excites the heart.
2.
The pacemaker must receive information from central and
peripheral chemoreceptors.
3.
In turn, the pacemaker should drive neurons which drive
muscles of inspiration and expiration.
38
How do inputs from central and peripheral
chemoreceptors reach respiratory motor neurons?
Pons
Medullary
chemoreceptors
Medulla
Afferents from
carotid bodies
terminate here
Pre-Bottzinger
complex; preBOTC
(Pacemaker)
I neurons
Diaphragm
Spinal
cord
Phrenic motor
neurons
39
Neural mechanism of spontaneous breathing:
(A hypothetical working draft..)
Pons
Medullary
chemoreceptors
Medulla
Afferents from
carotid bodies
terminate here
Pre-Bottzinger
complex; preBOTC
(Pacemaker)
I neurons
Diaphragm
Spinal
cord
Phrenic motor
neurons
40
Component
Details
Peripheral &
central
chemoreceptor
neurons
Project to Pre-Botzinger complex of
neurons (the putative pacemaker)
Neurons in preBOTC
•Discharge
spontaneously (pacemakers)
•Entrained by input from chemoreceptors
(i.e. frequency of discharge is modulated by input
from chemoreceptors)
I neurons
•Fire
during inspiration
•Project to lower motor neurons in spinal
cord (e.g. phrenic motor neurons)
41
Some more questions to be answered
about spontaneous breathing:


Our model explains the mechanism of spontaneous
inspiration.
But what is the mechanism of spontaneous expiration?
42
During spontaneous breathing, expiration
is due to passive elastic recoil of lung
Breathe in
Thorax expands
Lungs expand i.e.,
lung parenchyma is stretched
Elastic lungs recoil spontaneously
43
But there is a problem..

If I neurons continue to fire during expiration, then,
contraction of muscles of inspiration will oppose
expiration and increase the work of breathing.

So what?

Hypothesis: There could be a mechanism inhibiting
discharge of I neurons during expiration.
44
Interpret this experimental observation:
Normal breathing pattern
apneusis
Breathing after transection of neuraxis between pons and medulla
45
A center in the pons may serve to switch
from inspiration to expiration
(Hypothetical working draft model..)
Pons
-
Medulla
-
Pneumotaxic
center
Pre-Bottzinger
complex; preBOTC
(Pacemaker)
I neurons
Diaphragm &
intercostal
muscles
Spinal
cord
Phrenic neurons
46
But is there anything that drives the Pneumotaxic center
to cause the switch from Inspiration to Expiration?








How could we test it?
Suggest an experiment
Breathe in deep
Try breathing in further
Can you do it?
Do you find it difficult? Why?
Is a mechanism triggering expiration??
Note the duration of expiration is also longer
following a deep breath
47
This reflex is called Hering-Breuer inflation
reflex (stimulus: excessive lung inflation)


Experiment: Deep inspiration
Observation (response):





further inspiration is inhibited
expiration is triggered
the duration of this expiration is longer
this has been shown to be abolished by vagotomy
(cutting afferent input from stretch receptors in lungs to
pons & medulla)
Conclusion: vagal afferent input from lungs inhibits
excessive lung stretch (negative feedback)
48
So what is the pattern of breathing you expect
after vagotomy? Observations below..
Normal
After vagotomy
Note the depth of breathing is increased after vagotomy
49
Hering-Breuer deflation reflex
(Stimulus: excessive lung deflation)





Experiment: breathe out fully
Try breathing out even more
Observation: Can you do it? Why?
Note the depth of the next inspiration?
Response:



Further deflation is inhibited (negative feedback)
The next inspiration is prolonged.
The deep inspiration following a deep expiration
is abolished by vagotomy
50
take a look at this phenomenon..
Breathe in
This stimulates further lung inflation
+ / - feedback??
Positive feedback
A paradoxical reflex (Head’s paradoxical reflex)
Can you think of one situation in which it might be
“useful”?
51
The first cry – the most crucial moment in life
The cry of a newborn
Generates very negative
intrathoracic pressure
Facilitates expansion of
collapsed fluid filled lungs
Do Hering Breuer reflexes
work in this situation?
52
Summary:
Stimulus
Name of
reflex
Receptor
Excessive
Inhibition of
lung inflation inflation; lung
deflation
Hering
Breuer
inflation
reflex
Vagal
afferents
from
airways
Excessive
Inhibition of
lung deflation deflation; lung
inflation
Hering
Breuer
deflation
reflex
Vagal
afferents
from
airways
Head’s
paradoxical
reflex
?
Lung
inflation
Response
Further
inflation
53
Part 3
Take this problem:

If you gradually ascend to an altitude of 2500 m
and live there for a month, in which direction
would you expect the following variables to
change?




PaO2 – Increase / decrease. Why?
PaCO2 – Increase / decrease. Why?
pH of arterial plasma – Increase / decrease. Why?
Minute ventilation – Increase / decrease. Why?
55
Answer:







Low PaO2 due to low barometric pressure
This drives peripheral chemoreceptors
Minute ventilation is increased
PaCO2 will fall because of increased minute ventilation
Arterial pH raised because of increased elimination of CO2
Hypoxemia with respiratory alkalosis
Further question: what is the magnitude of the increase in
minute ventilation in response to hypoxemia?
56
The ventilatory response to hypoxia:
200
Minute
ventilation
(l/min)
100
0
0
25
50
75
PO2 (mm Hg)
100
57
Consider this situation:

If we perform moderate exercise (let us say bicycle) at
high altitude (2500 m) without being truly accustomed to
high altitude, how much would minute ventilation increase
during exercise?

Not at all / Increase / Increase greatly

Explain why??

And what will happen to our work capacity?

Decrease / not change / increase
58
Ventilatory response to hypoxia, hypercapnia, severe exercise and
maximal voluntary ventilation (MVV) compared
200
Minute
ventilation
(l/min)
100
MVV: 125-175 l/min
Max. ventilation during exercise
Response to hypercapnia
Response to hypoxia
0
0
50
100
Alveolar PO2 or PCO2 (mm Hg)
59
Answer:



Minute ventilation increases much more;
Stimuli for breathing: hypoxia + metabolic (lactic) acidosis;
We will be breathless and get exhausted quicker.
Regarding the graph in the previous slide:
•
•
•
•
•
At rest, minute ventilation is about 5 l/min
But MVV = 125-175 l/min (higher in males compared to
females)
Thus, there is a great ventilatory reserve (25 – 35 times);
Hypoxia and hypercapnia alone are not as potent as severe
exercise in stimulating ventilation.
So, other factors also drive ventilation during exercise.
60
Why do we get breathless during
exercise?




Besides activation of breathing by carotid bodies, suggest
some other potential mechanisms that may contribute to the
sensation of breathlessness during intense exercise…
What would be the effect of an increase in pulmonary
interstitial fluid pressure (PIFP) on breathing pattern? When
does this occur?
Clue: What happens to PIFP in heart failure?
What is the pattern of breathing in this condition?
61
Some working definitions now:





Normocapnia: PaCO2 between 35 and 45 mm Hg
Hypocapnia: PaCO2 < 35 mm Hg
Hypercapnia: PaCO2 > 45 mm Hg
Hypoxemia: PaO2 < 80 mm Hg
Note: significant activation of carotid bodies
occurs only when PaO2 < 60 mm Hg
62
This pattern of breathing (shown in brown) was
observed in a patient with brain stem disease. Can
you suggest a mechanism that can result in such a
breathing pattern?
Normal
63
Cheyne-Stokes respiration:
Periods of apnea punctuated by periods of
hyperpnea
It occurs in:




1.
2.
congestive heart failure
brain stem disease affecting respiratory centers
Mechanisms postulated to explain this:
Prolonged lung-to-brain circulation time
Alterations (increase or decrease) in sensitivity of
medullary chemoreceptor or respiratory neurons
64
What is the effect of voluntary hyperventilation
to exhaustion on breathing?



Hyperventilate to exhaustion
Then, note your pattern of breathing
Explain your observations.
65
Activity:
hyperventilation
Periodic breathing
normal
Following
hyperventilation
66
Outline of the explanation:








Hyperventilation eliminates CO2;
Apnea is due to lack of CO2
During apnea, PaO2 falls & stimulates breathing
Few breaths eliminate hypoxia
Now there is no stimulus for breathing
So there is apnea again
Normal breathing resumes only when PaCO2 is
40 mm Hg
Conclusion: normal breathing pattern is entrained
by PaCO2 not PaO2
67
Could one stay alive after respiratory
centers in the medulla are destroyed?


Yes / No
How?
68
Ondine’s curse:




Spontaneous control of breathing is disrupted;
Voluntary control is intact;
One could stay alive only by remembering to
breathe;
Clinical analog:


bulbar poliomyelitis affecting respiratory neurons in
the brain stem;
disease processes compressing the medulla
69
Some items for self-study:





How is breathing regulated during exercise?
What is the mechanism of hiccup?
What is the mechanism of yawning?
What is the mechanism of sneezing?
What happens when you sigh?
70
Now take the Post-Test
In addition, you should also be able to
answer these questions:
1.
Describe with the help of schematic diagram, the
neural mechanism of spontaneous breathing.
2.
Describe with the help of schematic diagram, the
neural mechanism of voluntary control of
respiration.
3.
Describe with the help of schematic diagram, the
role of systemic arterial chemoreceptors in
regulation of alveolar ventilation.
72
4.
Describe with the help of schematic diagrams the
functional organization and functions of medullary
chemoreceptors.
5.
How does CO2 stimulate breathing?
6.
What is the relationship between PaCO2 and minute
ventilation?
7.
Describe the mechanism responsible for periodic
breathing following voluntary hyperventilation.
73
8.
Explain the factors that affect breath holding time.
9.
Briefly explain the effect of damage to the
pneumotaxic center on the pattern of breathing
10.
Briefly explain the effect of vagotomy on the
pattern of breathing in experimental animals.
74
11.
12.
What is the difference between the effect of acute
hypercapnia and chronic hypercapnia on minute
ventilation?
What is Kussmaul’s respiration? When does it
occur? What is the mechanism involved?
13.
What is periodic breathing? When does it occur?
What is Cheyne-Stokes respiration?
14.
What are the Hering Breuer reflexes?
15.
What is Head’s paradoxical reflex?
75
Required reading:

Chapter 36. Regulation of respiration. Ganong
WF. Review of Medical Physiology, Mc Graw
Hill Co, 2005
76