1. Manuscript: Explicit Constructivism: a missing link in ineffective lectures? Author: E.S.Prakash Supplement 1: Typical Lecture
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2. Chemical and neural regulation of respiration
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. If you breathe 500 ml per breath 12 times a minute and your dead space is 150 ml, then, what is the amount of fresh gas supplied to your alveoli per minute?

5. Organization of content in these lectures:
Neural control of breathing
Neural control systems: functional organization
Chemoreceptors: functional organization
Classification of chemoreceptors
Ventilatory responses:
to changes in acid-base balance
To CO2 excess
To oxygen lack
Interaction of hypoxia and CO2

6. Content outline continued:
Nonchemical influences on respiration
Responses mediated by airway receptors
Responses mediated by receptors in the lung parenchyma
Coughing & sneezing
Regulation of respiration during sleep
Abnormal respiratory patterns

7. Neural control of breathing
There are 2 systems:
One for voluntary control
One for spontaneous breathing

8. System for voluntary control of breathing:
Regulator neurons located in cerebral cortex
When does this system work?
When we control our breathing voluntarily
Example: when you hold your breath
Example: when you hyperventilate
Pathway: From cerebral cortex to motor neurons in the spinal cord which supply muscles of respiration (diaphragm & intercostal muscles)

9. System for spontaneous control of breathing:
Breathing is mostly spontaneous
Breathing is rhythmic (rate as well as depth)
We are not aware that we are breathing
Location of respiratory center: medulla
Please see schematic on next slide

10. Mechanism of spontaneous breathing
Afferents from carotid bodies terminate here
Pons
Medullary chemoreceptors
Pre-Botzinger complex; pre-BOTC (Pacemaker)
Medulla
I neurons
Spinal cord
Diaphragm & intercostal muscles
Phrenic neurons

11. Component
Details
Central chemoreceptor neurons (sensory)
Project to Pre-Botzinger complex of neurons
Pre-BOTC
Discharge spontaneously; pacemaker neurons for breathing (like SA node in heart); entrained by input from chemoreceptors
I neurons
Fire during inspiration; thus the name; project to lower motor neurons (e.g. phrenic n.) that drive muscles of inspiration

12. Feedback to the respiratory center from lungs:
During inspiration,
lungs expand, and lung parenchyma is stretched;
stretch receptors are present here;
these are activated and convey information to the brain via sensory branches of vagus nerve

13. Role of pons in respiration:
There is an area called pneumotaxic center in the pons;
If this area is damaged, then, depth of inspiration is increased (see next slide)
So, this center may serve to switch breathing from inspiration to expiration
This switch works to inhibit I neurons during expiration

14. Effect of vagotomy on breathing rate and depth; note the increase in depth
Normal
After vagotomy

15. Effect of damage to the pneumotaxic center in vagotomized animals:
normal
After vagotomy
apneusis

16. Functional organization of chemoreceptors:
A rise in PCO2, a fall in pH or PO2 of arterial blood increases respiratory neuron activity in the medulla.
Stimulus: a change in blood chemistry …
Sensed by: receptors called chemoreceptors
Response: change in minute ventilation

17. Functional organization of chemoreceptors (contd.)
Location of chemoreceptors:
Central chemoreceptors (in medulla); also called medullary chemoreceptors
Arterial chemoreceptors (in carotid & aortic bodies); sometimes called peripheral chemoreceptors

18. Functional organization of chemoreceptors (contd.)
Innervation of peripheral (systemic arterial chemoreceptors);
Figure at Link:
Note carotid body is supplied by branch of IX nerve and aortic bodies are supplied by branch of X nerve.

19. Some facts about systemic arterial chemoreceptors:
There are 2 types of cells in the carotid body;
Type I glomus cells contain oxygen sensitive K channels (these are the chemoreceptors)
Type II cells are supporting cells
They have a very high blood flow
In carotid bodies, blood flow rate: 2000 ml/100 g tissue/min
For example, the brain gets 50 ml/100 g/min

20. Stimuli that activate peripheral chemoreceptors:
Low PaO2 (hypoxemia)
Drop in arterial pH (acidosis)
Rise in PaCO2 (hypercapnia)
Low blood flow through the receptors; i.e., when cardiac output and BP are low
Note: these receptors are very sensitive to drop in PaO2 (hypoxemia) compared to rise in PaCO2 (hypercapnia)

21. So what are the normal values of each?
Arterial Blood Gases & pH
Normal range
Arterial pH
7.35 – 7.45
Arterial PO2
81 – 100 mm Hg
Arterial PCO2
35 – 45 mm Hg

22. Central chemoreceptors (medullary chemoreceptors)
Location: brain stem, ventral surface of medulla
They are located near I neurons
They project to respiratory neurons
Central chemoreceptors and respiratory neurons are distinct
They are mainly sensitive to changes in PaCO2
A rise in PaCO2 effectively stimulates central chemoreceptors

23. 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

24. Central chemoreceptor neurons monitor the H+ ion concentration of brain ISF;
Greater the PaCO2, > the minute ventilation;
If you lower PaCO2, minute ventilation is lowered

25. Effect of addition of metabolic acid (e. g
Effect of addition of metabolic acid (e.g., lactic acid, on ventilation)
Example: lactic acidosis (metabolic acidosis)
Arterial pH is low (< 7.35);
Breathing is rapid and deep (Kussmaul’s respiration) and CO2 is blown off
This response is mediated by carotid bodies (peripheral chemoreceptors) and is lost if they are removed.

26. Effect of a rise in blood pH on minute ventilation
Example: metabolic alkalosis due to vomiting; i.e., loss of HCl;
Arterial pH is high (> 7.45)
Respiration is slowed; i.e., decrease in minute ventilation)
As a result PaCO2 gradually rises

27. What happens if more CO2 is produced as a result of metabolism?
More CO2 in blood as a result of ↑metabolism
Transient rise in PaCO2
Fall in CSF pH
Respiration is stimulated effectively
Steady state PaCO2 is normal

28. Ventilatory response to CO2 lack or excess
200
Minute ventilation (l/min)
100
Alveolar PCO2 (mm Hg)

29. Ventilatory response to oxygen lack:
200
Minute ventilation (l/min)
100
PO2 (mm Hg)

30. 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)

31. Comments: Normally, minute ventilation is about 5 l/min
MVV = l/min (higher in males cf. females)
Thus, there is a great ventilatory reserve;
But MVV can be sustained only for a short time
Hypoxia and hypercapnia alone are not as potent as severe exercise in stimulating ventilation
So, other factors also drive ventilation during exercise.

32. Interaction of ventilatory responses to CO2 and O2 (all partial pressures in mm Hg)
PAO2 = 40
100
PAO2 = 55 75
PAO2 = 100
Ventilation (l/min) 50 25 40
PACO2 50

33. Conclusion:
Conclusion: Hypoxia makes an individual more sensitive to CO2 excess

34. Ventilation at high altitudes:
Barometric (atmospheric) pressure is lower;
When PaO2 is < 60 mm Hg, min. ventilation ↑
What happens to PaCO2?
It is lowered as a result of hyperventilation
What happens to pH of arterial blood?
pH increases slightly say from 7.4 to 7.45
Arterial blood gases: Hypoxemia (low PaO2); hypocapnia (PaCO2 < 35 mm Hg); respiratory alkalosis (pH > 7.45 because of hypocapnia)

35. Some working definitions for you:
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

36. Effects of breath holding:
Respiration can be voluntarily inhibited for some time
Eventually, voluntary control is overridden (breaking point)
What is breaking due to?
Rise in PaCO2 (acute hypercapnia)
Fall in PaO2
Individuals can hold their breath longer after removal of carotid bodies;
Psychologic factors also contribute

37. Effects of hyperventilation:
Overbreathing to exhaustion;
Eventually there is a “breaking point”
Note a period of apnea following hyperventilation;
What is breaking here due to?
CO2 lack
apnea
Overbreathing

38. Effects of chronic hypercapnia:
When does chronic hypercapnia occur?
What is the basic cause of chronic hypercapnia?
Failure to eliminate CO2; (respiratory failure)
Reason: reduction in alveolar ventilation
Note:
acute hypercapnia stimulates breathing
chronic hypercapnia depresses the respiratory center

39. Nonchemical influences on respiration:
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 ?

40. Nonchemical influences on respiration (contd.):
Stimulus
Response
Name of reflex
Receptor
Lung hyperinflation; increase in pulmonary interstitial fluid pressure; or intravenous injection of capsaicin
Apnea followed by tachypnea; bradycardia; hypotension; skeletal muscle weakness
J reflex
Juxtacapillary receptors (C vagal fiber endings)
Injection of histamine
Cough, bronchoconstriction, mucus secretion
Cough reflex
Irritant receptor; among airway epithelial cells

41. Mechanism and significance of cough:
Deep inspiration
Forced expiration against a closed glottis
Intrathoracic pressure increases to 100 mm Hg or more
Glottis opened by explosive outflow of air
Airways are cleared of irritants

42. 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

43. Regulation of respiration during sleep:
Respiration is less rigorously controlled during sleep;
Brief periods of apnea occur even in normal people;
Ventilatory response to hypoxia varies;
Sensitivity of brain stem mechanisms reduced?

44. Abnormal breathing patterns: Periodic breathing (Cheyne-Stokes respiration)

45. 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
Changes in sensitivity of medullary respiratory neurons

46. Following hyperventilation
Activity:
Hyperventilate to exhaustion
Then, note your pattern of breathing
Explain your observations
Periodic breathing
hyperventilation
normal
Following hyperventilation

47. 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

48. Some items for self-study:
How is breathing regulated during exercise?
What is the mechanism of hiccups?
What is the mechanism of yawning?
What is the mechanism of sneezing?
What happens when you sigh?

49. POST-TEST

50. 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 the regulation of alveolar ventilation

51. 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

52. 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.

53. 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?

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