1. Regulation of breathing

2.  What makes the inspiratory muscles contract and relax rhythmically?  How could the respiratory activity be modified?  How could the expiratory muscles be called on during active expiration?  How could the arterial P O 2 and P CO 2 be maintained within narrow limits?  What is the role of the respiratory system in regulating blood H + concentration? What is This Lecture About?

3. The Neural & Chemical Control of Respiration To answer these questions we need to understand:

4. Neural control The motor neurons that stimulate the respiratory muscles are controlled by two major descending pathways: one that controls voluntary breathing and another that controls involuntary breathing. The unconscious rhythmic control of breathing is influenced by sensory feedback from receptors sensitive to the P CO 2, pH, and P O 2 of arterial blood.

5. Inspiration and expiration are produced by the contraction and relaxation of skeletal muscles in response to activity in somatic motor neurons in the spinal cord. The activity of these motor neurons is controlled, by descending tracts from neurons in the respiratory control centers in the medulla oblongata and from neurons in the cerebral cortex.

6. Neural control of Respiration Fairly normal ventilation retained if section above medulla Ventilation ceases if section below medulla  medulla is major rhythm generator The Rhythm: inspiration followed by expiration anterior

7. Neural control of Respiration It is believed that the breathing rhythm is generated by a network of neurons called the Pre- Brotzinger complex. These neurons display pacemaker activity. They are located near the upper end of the medullary respiratory centre

8. What gives rise to inspiration? PONS MEDULLA SPINAL CORD Dorsal respiratory group neurones (inspiratory) Fire in bursts Firing leads to contraction of inspiratory muscles - inspiration When firing stops, passive expiration

9. What about “active” expiration during hyperventilation? Increased firing of dorsal neurones excites a second group: Ventral respiratory group neurones Excite internal intercostals, abdominals etc Forceful expiration In normal quiet breathing, ventral neurones do not activate expiratory muscles

10. The rhythm generated in the medulla can be modified by neurones in the pons: “pneumotaxic centre” (PC) Stimulation terminates inspiration PC stimulated when dorsal respiratory neurones fire Inspiration inhibited - +

11. The “apneustic centre” Apneustic centre Impulses from these neurones excite inspiratory area of medulla Prolong inspiration Conclusion? Rhythm generated in medulla modified by inputs from pons

12. Reflex modification of breathing Pulmonary stretch receptors Activated during inspiration, afferent discharge inhibits inspiration - Hering-Breuer reflex Do they switch off inspiration during normal respiratory cycle? Unlikely - only activated at large >>1 -1.5 litre tidal volumes Maybe important in new born babies May prevent over-inflation lungs during hard exercise?

13. Chemical Control of Respiration  An example of a negative feedback control system  Chemoreceptors sense the values of the gas tensions central and peripheral central and peripheral  The activity of the respiratory centers is regulated by the O 2, CO 2 and H + content of the blood.

14. Chemical regulation of respiration Chemical regulation of respiration Central chemoreceptors Carbon dioxide and H + are most important.Carbon dioxide and H + are most important. CO 2 dissolves in cerebrospinal fluid (CSF) which bathes receptors sensitive to H + on the ventral aspect of the medulla. Stimulation of these receptors is responsible for about 70% of the increase in the rate and depth of respiration in response to increased CO 2. CO 2 dissolves in cerebrospinal fluid (CSF) which bathes receptors sensitive to H + on the ventral aspect of the medulla. Stimulation of these receptors is responsible for about 70% of the increase in the rate and depth of respiration in response to increased CO 2.  Respond to the [H + ] of the cerebrospinal fluid (CSF)  CSF is separated from the blood by the blood-brain barrier  Relatively impermeable to H + and HCO 3 -  CO 2 diffuses readily  CSF contains less protein than blood and hence is less buffered than blood

16. Increase in CO 2 increases H + concentration in CSF (CO2 + H2O in CSF H 2 CO 3 HCO 3 – + H +) Stimulates H + receptors Stimulates RESPIRATORY CENTERS Increases rate and depth of breathing Fall in blood CO 2 slightly depresses breathing

17. Сarotid and aortic bodies are responsible for the other 30% of the response to raised to CO 2.Сarotid and aortic bodies are responsible for the other 30% of the response to raised to CO 2. They also increase ventilation in response to a rise in H+ or a large drop in PaO 2 ( to below 60 mmHg).They also increase ventilation in response to a rise in H+ or a large drop in PaO 2 ( to below 60 mmHg).

19. Arterial PaO 2, normally 100 mmHg, has to fall to 60 mmHg to stimulate chemoreceptors.Arterial PaO 2, normally 100 mmHg, has to fall to 60 mmHg to stimulate chemoreceptors. Severe lack of O 2 depresses respiratory center.Severe lack of O 2 depresses respiratory center. CHEMO-REFLEXES:CHEMO-REFLEXES: in addition to the effect of CO 2 and O 2 on center, rise in H + of blood stimulates carotid and aortic bodies. Lack of O2 Stimulates CHEMORECEPTORS (‘Oxygen-lack’ receptors) in carotid body and aortic body Reflexly stimulates respiration

20. The chemical and nervous means of regulating the activity of respiratory centers act together to adjust rate and depth of breathing to keep the P a CO 2 close to 40 mmHg. This automatically sets the P a O 2 to an appropriate value depending on the partial pressure of O 2.The chemical and nervous means of regulating the activity of respiratory centers act together to adjust rate and depth of breathing to keep the P a CO 2 close to 40 mmHg. This automatically sets the P a O 2 to an appropriate value depending on the partial pressure of O 2. For example, exercise causes increased requirement for O 2 and the production of more CO 2. ventilation is increased to get rid of the extra CO 2 and keep the alveolar PaCO 2 at 40 mmHg. More oxygen is used by the tissues. The alveolar PO 2 and PCO 2 both remain constant.For example, exercise causes increased requirement for O 2 and the production of more CO 2. ventilation is increased to get rid of the extra CO 2 and keep the alveolar PaCO 2 at 40 mmHg. More oxygen is used by the tissues. The alveolar PO 2 and PCO 2 both remain constant.

21. Voluntary and reflex factor in the regulation of respiration There is a separate voluntary system for the regulation of ventilation. It originates in the cerebral cortex and sends impulses to the nerves of the respiratory muscles via the corticospinal tracts.There is a separate voluntary system for the regulation of ventilation. It originates in the cerebral cortex and sends impulses to the nerves of the respiratory muscles via the corticospinal tracts. In addition, ingoing impulses from many parts of the body modify the activity of the respiratory centers and consequently alter the outgoing impulses to the respiratory muscles to coordinate rhythm, rate or depth of breathing with other activities of the body.In addition, ingoing impulses from many parts of the body modify the activity of the respiratory centers and consequently alter the outgoing impulses to the respiratory muscles to coordinate rhythm, rate or depth of breathing with other activities of the body.

22. Proprioreceptors stimulated during muscle movements send impulses to respiratory center ↑↑ rate and depth of breathing.Proprioreceptors stimulated during muscle movements send impulses to respiratory center ↑↑ rate and depth of breathing. This occurs with active or passive movements of limbs.)This occurs with active or passive movements of limbs.) Peripheral proprioceptors found in muscles, tendons, joints, and pain receptorsPeripheral proprioceptors found in muscles, tendons, joints, and pain receptors Movement stimulates hyperpnea.Movement stimulates hyperpnea. Moving limbs, pain, cold water all stimulate breathing in patients with respiratory depressionMoving limbs, pain, cold water all stimulate breathing in patients with respiratory depression

23. Anesthesia greatly depresses the respiratory center J receptors A few sensory nerve endings in the alveolar walls in juxtaposition to the pulmonary capillaries They are stimulated when the pulmonary capillaries become engorged or when pulmonary edema occurs as in congestive heart failure. (their excitation may give the person a feeling of dyspnea).

24. Irritant Receptors in the Airways The epithelium of the trachea, bronchi, and bronchioles is supplied with sensory nerve endings called pulmonary irritant receptors when stimulated cause coughing and sneezing. They may also cause bronchial constriction in such diseases as asthma and emphysema.

25. Joint receptors  Impulses from moving limbs reflexly increase breathing  Probably contribute to the increased ventilation during exercise

26. Factors That May Increase Ventilation During Exercise  Reflexes originating from body movement  Increase in body temperature  Adrenaline release  Impulses from the cerebral cortex  Later: accumulation of CO 2 and H + generated by active muscles

27. Peripheral Chemoreceptors Carotid bodies Aortic bodies Sense tension of oxygen and carbon dioxide; and [H + ] in the blood

28. Hypoxic Drive of Respiration  The effect is all via the peripheral chemoreceptors  Stimulated only when arterial P O2 fall less than 60mmHg  Is not important in normal respiration  May become important in patients with chronic CO 2 retention (e.g. patients with COPD)  It is important at high altitudes

29. The H + Drive of Respiration  The effect is via the peripheral chemoreceptors  H + doesn’t readily cross the blood brain barrier (CO 2 does!)  The peripheral chemoreceptors play a major role in adjusting for acidosis caused by the addition of non- carbonic acid H + to the blood (e.g. lactic acid during exercise; and diabetic ketoacidosis)  Their stimulation by H + causes hyperventilation and increases elimination of CO 2 from the body (remember CO 2 can generate H +, so its increased elimination help reduce the load of H + in the body)  This is important in acid-base balance

30. In summary very marked increase in ventilation caused by an increase in Pco2 in the normal range between 35 and75 mm Hg. By contrast, the change in respiration in the normal blood pH range between 7.3 and 7.5 is less than one tenth as great.

31. Changes in oxygen concentration have virtually no direct effect on the respiratory center itself to alter respiratory drive (although oxygen changes do have an indirect effect, acting through the peripheral chemoreceptors

32. Abnormal Breathing Patterns Apnea Absence of breathing. (Ap-knee-a) Eupnea Normal breathing (Eup-knee-a) Orthopnea Only able to breathe comfortable in upright position (such as sitting in chair), unable to breath laying down, (Or-thop-knee-a) Dyspnea Subjective sensation related by patient as to breathing difficulty.

33. Hyperpnea Increased volume with or without and increased frequency (RR), normal blood gases present

35. "Over" ventilation - ventilation in excess of the body's need for CO2 elimination. Results in a decreased PaCO2, and a respiratory alkalosis Hyperventilation "Over" ventilation - ventilation in excess of the body's need for CO2 elimination. Results in a decreased PaCO2, and a respiratory alkalosis

37. Hypoventilation. Decreased rate (A) or depth (B), or some combination of both. "Under" ventilation - ventilation that is less than needed for CO2 elimination, and inadequate to maintain normal PaCO2. Results in respiratory acidosis.

39. Tachypnea Increased frequency without blood gas abnormality. Cheyne-Stokes respirations Gradual increase in volume and frequency, followed by a gradual decrease in volume and frequency, with apnea periods of 10 - 30 seconds between cycle

40. Regulation of Respiration During Exercise In strenuous exercise, O 2 consumption and CO 2 formation can increase as much as 20-fold. in the healthy athlete,alveolar ventilation ordinarily increases almost exactly in step with the increased level of oxygen metabolism. The arterial Po 2, Pco 2, and pH remain almost exactly normal.

41. Chemical Factors and Nervous: in the Control of Respiration During Exercise Direct nervous signals stimulate the respiratory center almost the proper amount to supply the extra oxygen required for exercise and to blow off extra carbon dioxide; Then chemical factors play a significant role in the final adjustment of respiration required to keep the oxygen, carbon dioxide, and hydrogen ion concentrations of the body fluids as nearly normal as possible.

42. What causes intense ventilation during exercise? The brain, on transmitting motor impulses to the exercising muscles at the same time collateral impulses into the brain stem to excite the respiratory center. This is analogous to the stimulation of the vasomotor center of the brain stem during exercise that causes a simultaneous increase in arterial pressure.