1. Phol 480: Pulmonary Physiology Section Session 3: Control Instructor Jeff Overholt e-mail: jxo@po.cwru.edu phone: 8962 location: E616 Medical School Text: Berne and Levy, Fourth ed. Chapter 36 Powerpoint Presentations: are on Frank Sonnichsen’s lab home page. Go to the Department of Physiology and Biophysics page, go to Faculty and click on Frank’s 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: O 2 Transport: One liter of plasma holds only 3 ml of O 2 (at PO 2 of 100 mmHg). This is not sufficient to supply the metabolic consumption of O 2,which is about 250 ml/min. Therefore higher organisms developed a special molecule to aid in O 2 transport in the blood: Hemoglobin (Hb) Each hemoglobin molecule can bind 4 O 2 molecules, and binding is cooperative. This gives hemoglobin a sigmoidal saturation curve. Hb is saturated with PO 2 's above 60-70 mmHg (flat upper portion of saturation curve). Steep part of curve reflects the range of PO 2 ‘s over which hemoglobin will release O 2.

3. Transport of CO 2 : CO 2 is transported in three forms. 1. Dissolved in plasma (~7%) 2. Combined with hemoglobin (~25%) 3. Carbonic Acid (~70%). In the Tissues:In the Lungs:

4. Alveolar Ventilation: The quantity of air moved into and out of the alveoli each minute Alveolar Ventilation Equation: Where V A is alveolar ventilation (L/min), V CO2 is the metabolic production of CO 2 and PA CO2 is alveolar PCO 2 and K is a constant (0.863 mmHg x L/min). This equation shows the intimate relationship between alveolar CO 2 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 PCO 2 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 PO 2 and PCO 2 constant. The venous PO 2 and PCO 2 can change considerably during periods of increased demand/usage as in exercise. 2) How do we maintain PO 2 and PCO 2 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. PCO 2 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 (O 2, CO 2, pH) and physical factors. A. Central: The main stimulus to central chemosensitivity is CO 2. -CO 2 is a much more sensitive measure because normal O 2 delivery occurs over a wide range of ventilation. (Hb is saturated well below normal PO 2 at sea level). -There is little direct effect of O 2 on the respiratory center.

13. Central Control (cont’d): 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 CO 2 in the blood have a bigger effect on the chemosensitive area because CO 2 can easily cross the blood brain and blood cerebrospinal fluid barriers. However, CO 2 itself has very little direct effect on the chemosensitive area. Rather, CO 2 reacts with water to form carbonic acid, which dissociates into H + and HCO 3 -. Therefore, more H + is released into the chemosensitive area when blood PCO 2 increases than when blood H + increases, and consequently blood PCO 2 has more effect on respiration than blood pH. However, the effect of CO 2 is an acute effect, that is it declines after a few hours. -The kidneys increase HCO 3 - 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 O 2. (Remember, there is very little stimulatory effect of O 2 in the central chemosensitive area. Rather, in central neurons, hypoxia (low O 2 ) depresses breathing. Also sense arterial CO 2 and are responsible for ~25% of the CO 2 drive to the central respiratory generator. The peripheral chemoreceptors respond rapidly to CO 2 and are probably responsible for the immediate (first few breaths) response to CO 2. 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 (cont’d): 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 O 2 in the 30-60 mmHg range.

16. Carotid Bodies (cont’d): The carotid body is highly vascular. The blood flow rate is 20X their weight/min. This means that there is essentially no removal of O 2 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 16:299-308, 1973.

18. Carotid Bodies (cont’d): How is O 2 sensed by glomus cells? One possible hypothesis: In glomus cells, potassium channels have been identified that are sensitive to O 2.

19. Sensory Activity Carotid Sinus Nerve Ca 2+ K+K+ K+K+ Depolarization (+) Hypoxia (-) (+) (-) E I Second Messenger Pathways Glomus Cell K + Channel Hypothesis: K + channels set the resting membrane potential because they are open at that potential. Decreasing arterial O 2 decreases K + current, causing the membrane to depolarize Depolarization causes opening of Ca 2+ channels. Opening of Ca 2+ channels increases intracellular Ca 2+ 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 O 2 and CO 2 are synergistic: This is a paradox, i.e. when you lower arterial PO 2 and stimulate breathing via the carotid body, the increased breathing decreases the arterial PCO 2. The decreased PCO 2 depresses the central chemosensitive area and therefore the overall effect of low PO 2 on respiration is decreased. There is a much greater effect of changes in arterial PO 2 when PCO 2 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. CO 2 /O 2 Interactions (cont’d):

22. Overall Picture of O 2 and CO 2 Interactions: Solid line represents the effect of PCO 2 on ventilation at pH 7.4 with different PO 2 values. Comparing these lines shows the effect of changing PO 2 on the ventilatory effect of PCO 2. Dashed line represents the effect of PCO 2 on ventilation at pH 7.3 while varying the PO 2. Comparing the solid lines and the dashed lines indicates the effect of pH. *lower PO 2, greater effect of PCO 2 on ventilation. *lower pH, greater effect of PCO 2 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 PCO 2 increases There is a decrease in both threshold and sensitivity to CO 2. The sensitivity to O 2 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 PO 2 and a decrease in PCO 2 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 PCO 2 in the blood in the chemosensitive areas in the brain, not in the pulmonary blood.

29. Cheyne-Stokes Breathing (cont’d): 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 PCO 2 and PO 2 -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 O 2 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 O 2 delivery to the cells is adequate to match mitochondrial requirements.

31. Ventilation and Exercise (cont’d): 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 O 2 consumption and CO 2 production. The arterial PO 2, PCO 2 and pH remain unchanged.

32. Ventilation and Exercise (cont’d): However, measurements of arterial PCO 2, PO 2 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 (cont’d): Exercise shifts the alveolar CO 2 ventilation response curve.

34. High Altitude and Breathing:

36. To look at it another way: The control of a physiological system can be compared to a physical plant system.