1. Manuscript: Explicit Constructivism: a missing link in ineffective lectures? Author: E.S.Prakash Supplement 2: Constructivist Lecture
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2. Chemical and neural regulation of respiration (a block of 3 lectures)
E.S.Prakash, School of Medicine, AIMST University, Malaysia

3. How much do we already know
How much do we already know? Just write the answers with the question number on a sheet of paper
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:

4. 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?

5. 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

6. So, logically, the system that regulates breathing should do the following:
It MUST sense oxygen concentration in blood;
It COULD sense oxygen concentration in cells;
It MUST sense pH of blood and body fluids;
It MUST be able to initiate appropriate responses so that the above parameters are maintained within acceptable limits.

7. 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.

8. 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.

9. 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)

10. Arterial chemoreceptors SENSE…
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

11. Sensory innervation of arterial chemoreceptors:
Aortic bodies
Sensory branches of X cranial n.
Carotid bodies
Sensory branch of IX cranial n.

12. 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?

13. So what are the normal values of each?
Parameter
Normal range
Arterial pH
7.35–7.45
Arterial PO2 (PaO2)
81–100 mm Hg
Arterial PCO2 (or PaCO2)
35–45 mm Hg

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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.

20. Can you suggest an animal experiment to test this question?
We said that a rise in PaCO2 would increase minute ventilation. How is this response mediated? Is this mediated by the carotid bodies?
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?

21. 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!

22. 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”)

23. 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?

24. CO2 crosses the blood brain barrier (BBB)
A rise in PaCO2 lowers CSF pH which is sensed by medullary chemoreceptors
CO2 crosses the blood brain barrier (BBB)
CO2
blood
brain ISF
H+ + HCO3
CO2 + H2O
H2CO3
Carbonic anhydrase
Drop in CSF pH

25. 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?

26. Continued >> CO2 is buffered mainly by:
hemoglobin
plasma proteins
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?
20 mg/dL
CSF has times less protein (buffering capacity) compared to plasma

27. 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.

28. 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)

29. Mediate the ventilatory response to a rise in PaCO2
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

30. Continuing from where we left off..
Part Two..
Continuing from where we left off..

31. 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?

32. 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?

33. 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?

34. 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]

35. 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.

36. 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

37. 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
NB: There are both excitatory as well as inhibitory controls from cerebral cortex
Spinal cord
+/-
Phrenic n.
Intercostal n.
Muscles of expiration:
Internal intercostals
Diaphragm
Intercostal n.
External intercostals

38. How do you expect spontaneous breathing to be achieved?
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.
The pacemaker must receive information from central and peripheral chemoreceptors.
In turn, the pacemaker should drive neurons which drive muscles of inspiration and expiration.

39. Afferents from carotid bodies terminate here
How do inputs from central and peripheral chemoreceptors reach respiratory motor neurons?
Afferents from carotid bodies terminate here
Pons
Medullary chemoreceptors
Pre-Bottzinger complex; pre-BOTC (Pacemaker)
Medulla
I neurons
Spinal cord
Phrenic motor neurons
Diaphragm

40. Afferents from carotid bodies terminate here
Neural mechanism of spontaneous breathing: (A hypothetical working draft..)
Afferents from carotid bodies terminate here
Pons
Medullary chemoreceptors
Pre-Bottzinger complex; pre-BOTC (Pacemaker)
Medulla
I neurons
Spinal cord
Phrenic motor neurons
Diaphragm

41. Component
Details
Peripheral & central chemoreceptor neurons
Project to Pre-Botzinger complex of neurons (the putative pacemaker)
Neurons in pre-BOTC
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)

42. 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?

43. 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

44. 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.

45. Interpret this experimental observation:
Normal breathing pattern
apneusis
Breathing after transection of neuraxis between pons and medulla

46. Diaphragm & intercostal muscles
A center in the pons may serve to switch from inspiration to expiration (Hypothetical working draft model..)
Pneumotaxic center -
Pons
Pre-Bottzinger complex; pre-BOTC (Pacemaker)
Medulla -
I neurons
Spinal cord
Diaphragm & intercostal muscles
Phrenic neurons

47. 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

48. 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)

49. So what is the pattern of breathing you expect after vagotomy
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

50. 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

51. 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”?

52. 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?

53. Summary: Stimulus Response Name of reflex Receptor
Excessive lung inflation
Inhibition of inflation; lung deflation
Hering Breuer inflation reflex
Vagal afferents from airways
Excessive lung deflation
Inhibition of deflation; lung inflation
Hering Breuer deflation reflex
Lung inflation
Further inflation
Head’s paradoxical reflex ?

54. Part 3

55. 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?

56. 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?

57. The ventilatory response to hypoxia:
200
Minute ventilation (l/min)
100
PO2 (mm Hg)

58. 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

59. Max. ventilation during exercise
Ventilatory response to hypoxia, hypercapnia, severe exercise and maximal voluntary ventilation (MVV) compared
200
Minute ventilation (l/min)
MVV: l/min
Max. ventilation during exercise
100
Response to hypercapnia
Response to hypoxia
Alveolar PO2 or PCO2 (mm Hg)

60. Answer: Regarding the graph in the previous slide:
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 = 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.

61. 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?

62. 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

63. 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

64. Cheyne-Stokes respiration:
Periods of apnea punctuated by periods of hyperpnea
It occurs in:
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

65. What is the effect of voluntary hyperventilation to exhaustion on breathing?
Hyperventilate to exhaustion
Then, note your pattern of breathing
Explain your observations.

66. Following hyperventilation
Activity:
Periodic breathing
hyperventilation
normal
Following hyperventilation

67. 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

68. Could one stay alive after respiratory centers in the medulla are destroyed?
Yes / No
How?

69. 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

70. 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?

71. Now take the Post-Test

72. In addition, you should also be able to answer these questions:
Describe with the help of schematic diagram, the neural mechanism of spontaneous breathing.
Describe with the help of schematic diagram, the neural mechanism of voluntary control of respiration.
Describe with the help of schematic diagram, the role of systemic arterial chemoreceptors in regulation of alveolar ventilation.

73. Describe with the help of schematic diagrams the functional organization and functions of medullary chemoreceptors.
How does CO2 stimulate breathing?
What is the relationship between PaCO2 and minute ventilation?
Describe the mechanism responsible for periodic breathing following voluntary hyperventilation.

74. Explain the factors that affect breath holding time.
Briefly explain the effect of damage to the pneumotaxic center on the pattern of breathing
Briefly explain the effect of vagotomy on the pattern of breathing in experimental animals.

75. 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?
What is periodic breathing? When does it occur? What is Cheyne-Stokes respiration?
What are the Hering Breuer reflexes?
What is Head’s paradoxical reflex?

76. Required reading:
Chapter 36. Regulation of respiration. Ganong WF. Review of Medical Physiology, Mc Graw Hill Co, 2005