THE "REGULATION OF RESPIRATION" PAGE!
Control of Respiration by the Nervous System
1) A respiratory center within the reticular formation (network) of the medullary pons of the brainstem (with 3 centers as outlined below)
2) Chemoreceptors which send afferent or sensory input to the respiratory centers in the brainstem. There are peripheral and central brainstem chemoreceptors.
3) Neural reflexes which can modify the basic setup.
The 3 Medullary Centers Controlling Respiration
1) Bilaterally, on either side of the reticular formation are the medullary respiratory centers; an inspiration center and an expiration center send nerve impulses to the diaphragm and intercostal muscles. These respiratory centers (inspiration and expiration centers) are sometimes called the "medullary rhythmicity" centers, as they are believed to set the baseline rhythm for respiration. In the normal resting state, respiration is due to the inspiratory center and when these nerves shut off, there is passive exhalation. The expiration center is only required when activity and requirements are increased. In this diagram, you can see that the inspiratory center receives information from stretch receptors in the lungs via cranial nerve X, from peripheral chemoreceptors in the region where cranial nerves IX & X leave the brainstem and from pH and pCO2 receptors in the bone-dura-arachnoid-CSF space (more on these chemoreceptors, below).
The neurons of the inspiratory center are sometimes referred to as the Dorsal Respiratory Group (DRG) neurons, as the majority of inspiratory neurons are in the dorsal area of the brainstem. While most neurons of the expiratory group are found in the Ventral Respiratory Group (VRG), there is evidence of some inspiratory neurons in the Ventral Respiratory Group as well. Note that when your ventilation requirements are increased, as during exercise, your inspiratory center can suppress activity of the expiratory center while you inhale, and the expiratory center can suppress activity of the inspiratory center while you exhale (ie. reciprocal inhibition).
2) The next center up in the pons is the apneustic center, another reticular formation. Apneusis refers to an inspiratory gasp. The apneustic center facilitates inspiration... for example, the apneustic center may prolong inspiration when your oxygen requirements become elevated, as during exercise. In this sense, the apneustic center helps to control depth of respiration. If the brainstem is cut just above the apneustic center, apneustic breathing patterns will be induced (stop breathing, then inspiratory gasps). Generally, the apneustic center kicks the inspiratory center into gear if you go too long without breathing (for example, if you were very tired). Your inspiratory center can get sleepy, like other parts of the CNS!
3) The pneumotaxic center is located in the cranial part of the pons. This area controls the other 2 centers and cuts off inspiration at a certain point to make sure that inspiration does not continue too long. In this sense, the pneumotaxic center helps to control rate of respiration. For example, let's say you were exercising really strenuously and your inspiratory center was so hyperstimulated that it was still trying to make you inhale when your lungs were already fully inflated; you need the pneumotaxic center to shut off the inspiratory center in such a case so that you can keep ventilating the lungs!
If respiratory chemoreceptors were not functional, hypoxia would result; no matter what happens, the subject would breathe at a normal, resting rate!
1) Central Chemoreceptors are located on both sides of the medulla where cranial nerves IX (glossopharyngeal nerves) and X (vagal nerves) leave the brain. These chemoreceptors are primarily sensitive to pCO2 and the pH of blood. As pH falls (gets more acidic) and pCO2 levels rise, these chemoreceptors provide stimulatory inputs to the inspiratory center; this increases ventilation in an attempt to reduce H+ and CO2 in the blood. The chemoreceptors are actually located in the interstitial space, outside of the blood-brain barrier. As H+ ions cannot diffuse through the blood-brain barrier, the ability of decreased pH to stimulate respiration is due to H+ ions combining with bicarbonate ions to form carbonic acid, which diffuses through the blood-brain barrier, some of which dissociates to release H+ ions in the interstitium.
In fact, the presence of carbon dioxide and H+ are so critical to maintaining normal respiration, that if someone hyperventilates long enough, they will reduce carbon dioxide so much that they may faint. This is primarily because of the important role of carbon dioxide in maintaining peripheral blood pressure. Carbon dioxide strongly stimulates constriction of arterioles. When carbon dioxide levels drop with hyperventilation, blood vessels relax, peripheral blood pressure falls, and less blood and oxygen are delivered to the brain. If the level of oxygen in the brain falls low enough, you pass out. A little bit different than passing out if you hold your breath too long, in which case you just deplete oxygen in the blood. In both cases, consciousness is lost because of lack of available oxygen for the brain.
2) Remember that the dura mater, arachnoid and pia mater surround the entire CNS, not just the spinal cord! The Bone-Dura-Arachnoid-CSF space has a pH of 7.32. This is just slightly more acidic than the pH of arterial (7.40) and venous (7.38) blood. When the pCO2 is increased in the bloodstream, CO2 diffuses easily into the CSF space. Chemoreceptors on the surface of the medulla sense this increase in CO2 in the CSF and this may be indirectly due to the resultant decrease in pH. These chemoreceptors increase respiratory rate to remove CO2 from the blood and eventually from the CSF by increasing ventilation.
3) Peripheral Chemoreceptors known as the Aortic Bodies in the aortic arch and the Carotid Bodies (by the carotid baroceptors) at the bifurcation of the carotid arteries in the neck monitor pO2. The Aortic Bodies are supplied by the vagus nerve, the Carotid Bodies are supplied by the glossopharyngeal nerve. These pO2 receptors send nerve impulses to the medulla to increase respiration when pO2 falls. These centers are actually sensitive to both PO2 and pH.
Figure: Carotid Body O2 Receptors (Peripheral Receptors)
Suppose we record nerve impulses transmitted from the carotid bodies via cranial nerve 9 (ie. the glossopharyngeal nerve). Not until you get 650 nerve impulses/sec do the Carotid Bodies tell the brain to increase respiration rate. Note that in order for the Carotid Bodies to generate a signal frequency this high, the pO2 in arterial circulation would have to fall to levels as low or lower than the pO2 normally seen in venous circulation.
Generally, then, the oxygen chemoreceptors are not significantly involved in regulation of respiration. They may, however, be of functional value at extremely high elevations where O2 is "thin," as well as in patients suffering from chronic airway limitations (CAL). The term CAL may generally be preferred over the terms "obstructive" (ie. COPD) or "narrowing" as the term "limitation" covers many possible causes of impaired airway function. pO2 receptors become increasingly functional in CAL patients who suffer chronic elevations in pCO2 and H+. As these patients become progressively less responsive to elevated pCO2 and H+, they become increasingly sensitive to hypoxia, such that the pO2 receptors in these patients provide respiratory drive! This becomes a conundrum when working with CAL patients (including COPD patients), as administration of O2 may reduce their respiratory drive! Nonetheless, if O2 must be administered to save the COPD patient's life, it must be administered! If administering O2 to a COPD patient, one must be prepared to force ventilate, if necessary, or to ween the patient off the supplementary O2.
One important point to note is that when oxygen levels in the blood become increasingly deficient, for example following an injury impairing respiration, the general effect is to reduce activity of the central nervous system, including the brainstem. A pathological deficiency in oxygen can, therefore, decrease activity of the respiratory centers, further decreasing blood oxygen levels.
The Herring-Breuer Reflex (sometimes called "the inflation reflex")
Remember that all of the air conducting pathway, from the bronchi to terminal bronchioles, has smooth muscle! The Herring-Breuer Reflex, based on smooth muscle of the bronchi and bronchioles (ie. the smooth muscle of the conducting pathways), affects depth of respiration. The smooth muscle of the conducting pathways has stretch receptors. When excessively stretched, the stretch receptors send impulses to the brain to terminate inspiration. This is a protective reflex to prevent over-expansion of the lung; the stretch receptors are not used during normal respiration but become increasingly active with labored breathing associated with vigorous exercise or climbing. Again, the Herring-Breuer Reflex is protective only and is not used during normal respiration. The Herring-Breuer reflex probably functions in coordination with the pneumotaxic center to prevent overstretch of the lungs.
Effect of Peripheral Stretch Receptors (proprioceptors) on Respiration
When we exercise, we may experience an increase in depth and rate of respiration to meet the increased oxygen requirement. But the increase in respiration often precedes the actual increased oxygen requirement!!! There are probably at least 2 components to this increase in respiration that precedes the increased oxygen requirement. The first component is "anticipation of exercise" and may involve activation of the sympathetic nervous system. The second component involves activation of stretch receptors (proprioceptors) in skeletal muscle and joints (tendon organs). Increased activity of stretch receptors is detected by the medulla, and results in increased rate and depth of respiration. The effect is very rapid, and shows an "added value" to stretching before exercise (ie. in addition to heating up muscles and connective tissues and reducing stretch-related injuries).
CO2 and ventilatory drive:Normally, ambient air is approximately 0.3% CO2. If you inspire air with 5% CO2, rather than 0.3% CO2, ventilation rate will virtually double and continue to rise with further increases in the CO2 content of inspired air. Inspiration will plateau at volumes as great as 30 L/minute at approximately 15% CO2. Increasing the CO2 content of inspired air above 15% will not cause further increases in ventilation. Generally, then, increased CO2 means increased ventilation; decreased CO2 means decreased ventilation.
Figure: Pulmonary Ventilation/Alveolar PCO2 curves
Drugs associated with respiratory failure: Narcotics, barbiturates and opiates have direct effects on the respiratory center. They cause a right curve shift in the Pulmonary Ventilation/Alveolar PCO2 curve shown above. The shift in the curve is shown below! This means that pCO2 stimulation of respiratory drive is weakened when these drugs are used or abused (eg. Meperidine = Demerol = Narcotic; shifts ventilation/PCO2 curve to the right).
Note: Again, PO2 must drop very low (to about 40 mmHg) in order to stimulate respiration (an effect seen primarily at high altitudes where O2 tension is low). However, if CO2 in the alveolar gas is increased, O2 can stimulate ventilation at a pO2 higher than it normally would. This shift is depicted in the figure immediately below! What does this mean; yes, elevated pCO2 and reduced pH remain the major stimuli for respiration, but when you breathe in air with elevated CO2, your carotid chemoreceptors for pO2 begin to send out signals at a higher frequency and may begin to have a stimulatory effect on ventilation! Note that the partial pressure of O2 can only exert effects on respiration through peripheral chemoreceptors; if these peripheral O2 receptors are removed or damaged, respiration will never change in response to changes in pO2 anywhere in the body.
Fig. Pulmonary Ventilation/Alveolar PO2 – effect of increasing PCO2
Shallow Water Blackout!
This is a good time to talk about shallow water blackout. It sometimes leads to this!
If we hyperventilate before jumping into the water, we reduce pCO2 and increase pH, reducing our respiratory drive. We start swimming around underwater, burning off our O2 supply. Even though we are becoming hypoxic, we don't feel the urge to breathe as our pCO2 is still low after having hyperventilated! The next thing we know, we pass out from hypoxia and if someone isn't there to fish us out of the water and we don't regain consciousness, we drown!
Recall that the parasympathetic system causes bronchoconstriction, reducing anatomic dead space and optimizing ventilation of the lung while at rest. The sympathetic system causes bronchodilation to reduce airway resistance when ventilatory requirement is increased, as during exercise or climbing.
Don't forget... the cerebral cortex can voluntarily over-ride the medullary respiratory centers, at least temporarily. You can voluntarily adjust the depth and rate of respiration, and you can hold your breath and hyperventilate, at least for a while. Remember, also, if you hold your breath long enough, or hyperventilate long enough, you will pass out... at which time your ventilation rates will usually quickly return to normal.
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Revised: January 05, 2009