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The respiratory control system normally reacts very effectively to alterations in the internal “chemical” environment of the body. Changes in the body

, pH, and

usually result in alterations in alveolar ventilation that return these variables to their normal values. Special neurons called
chemoreceptors alter their activity when their own local chemical environment changes and can therefore supply the central respiratory controller with the afferent information necessary to make the appropriate adjustments in alveolar ventilation to change the whole-body

, pH, and

.

The respiratory control system therefore functions as a
negative-feedback system.
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The arterial and cerebrospinal fluid partial pressures of carbon dioxide are probably the most important inputs to the ventilatory control system in establishing the breath-to-breath levels of tidal volume and ventilatory frequency. (Of course, changes in carbon dioxide lead to changes in hydrogen ion concentration, and so the effects of these 2 stimuli can be difficult to separate.) An elevated level of carbon dioxide is a very powerful stimulus to ventilation: Only voluntary hyperventilation and the hyperpnea of exercise can surpass the minute ventilations obtained with hypercapnia. However, the arterial

is so precisely controlled that it normally changes little (< 1 mm Hg) during exercise strenuous enough to increase metabolic carbon dioxide production 10-fold.
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Acutely increasing the levels of carbon dioxide in the inspired air (the

) increases minute ventilation. The effect is most pronounced with

in the range of 0.05 to 0.10 (5%–10% CO
2 in inspired gas), which produces alveolar

between about 40 and 70 mm Hg. Above 10% to 15% CO
2 in inspired air, there is little further increase in alveolar ventilation: Very high arterial

(> 70–80 mm Hg) may directly produce respiratory depression. (Very
low arterial

caused by hyperventilation may temporarily cause apnea because of decreased ventilatory drive. Metabolically produced carbon dioxide will then build up and restore breathing.)
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The physiologic response to elevated carbon dioxide is dependent on its concentration. Low concentrations of carbon dioxide in the inspired air are easily tolerated, with an increase in ventilation the main effect. Greater levels cause dyspnea, severe headaches secondary to the cerebral vasodilation caused by the elevated

, restlessness, faintness, and dulling of consciousness, in addition to greatly elevated alveolar ventilation. A loss of consciousness, muscular rigidity, and tremors occur at inspired CO
2 concentrations greater than 15%. With 20% to 30% inspired carbon dioxide, generalized convulsions are produced almost immediately.
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The ventilatory response of a normal conscious person to physiologic levels of carbon dioxide is shown in Figure 9–4.

Inspired concentrations of carbon dioxide or metabolically produced carbon dioxide producing alveolar (and arterial)

in the range of 38 to 50 mm Hg increase alveolar ventilation linearly. The slope of the line is quite steep; it varies from person to person, with a mean slope of 2.0 to 2.5 L/min per mm Hg

for younger healthy adults. The slope decreases with age.
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Figure 9–4 also shows that hypoxia potentiates the ventilatory response to carbon dioxide. At lower arterial

(eg, 35 and 50 mm Hg), the response curve is shifted to the left and the slope is steeper. That is, for any particular arterial

, the ventilatory response is greater at a lower arterial

. This may be caused by the effects of hypoxia at the chemoreceptor itself or at higher integrating sites; changes in the central acid-base status secondary to hypoxia may also contribute to the enhanced response.
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Other influences on the carbon dioxide response curve are illustrated in Figure 9–5. Sleep (see Chapter 11 for more on sleep and the respiratory system.) shifts the curve slightly to the right. The arterial

normally increases during slow-wave sleep, rising as much as 4 to 5 mm Hg during deep sleep. Because of this rightward shift in the CO
2 response curve during non-REM sleep and other evidence, it is possible that there is a “wakefulness” component of respiratory drive. During non-REM sleep, chemoreceptor input could therefore constitute the sole respiratory drive. A depressed response to carbon dioxide during sleep may be involved in
central sleep apnea, a condition characterized by abnormally long periods (10–30 seconds) between breaths during sleep. This lack of central respiratory drive is a potentially dangerous condition in both infants and adults. (In
obstructive sleep apnea the central respiratory controller does issue the command to breathe, but the upper airway is obstructed because the pharyngeal muscles do not contract properly, there is too much fat around the pharynx, or the tongue blocks the airway.) Narcotics and anesthetics may profoundly depress the ventilatory response to carbon dioxide. Indeed, respiratory depression is the most common cause of death in cases of overdose of opiate alkaloids and their derivatives, barbiturates, and most anesthetics. Endorphins also depress the response to carbon dioxide.
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Chronic obstructive lung diseases depress the ventilatory response to hypercapnia, in part because of depressed ventilatory drive secondary to central acid-base changes, and because the work of breathing may be so great that ventilation cannot be increased normally. Metabolic acidosis displaces the carbon dioxide response curve to the left, indicating that for any particular

, ventilation is increased during metabolic acidosis.
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As already discussed, the respiratory control system constitutes a negative-feedback system. This is exemplified by the response to carbon dioxide. Increased metabolic production of carbon dioxide increases the carbon dioxide brought to the lung. If alveolar ventilation stayed constant, the alveolar

would increase, as would arterial and cerebrospinal

. This stimulates the central and arterial chemoreceptors (see the next section) and increases alveolar ventilation. Increased alveolar ventilation decreases alveolar and arterial

, as was discussed in
Chapter 3 (see
Figure 3–10), returning the

to the original value, as shown in
Figure 9–6.
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The curve labeled A in Figure 9–6 shows the effect of increasing ventilation (here

, or the inspired minute volume in liters per minute) on the arterial

. Note that the independent variable for curve A is on the
ordinate and that the dependent variable is on the abscissa. This graph is really the same as that shown in the upper part of
Figure 3–10. Curve B is the steady-state ventilatory response to elevated arterial

as obtained by increasing the percentage of inspired carbon dioxide—that is, it is a typical CO
2 response curve (like that seen in
Figure 9–4). The point at which the 2 curves cross is the “set point” for the system, normally a

of 40 mm Hg.
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As can be seen in Figure 9–7, the respiratory control system constitutes a negative-feedback system, with the

, pH, and

the controlled variables. To act as a negative-feedback system, the respiratory controller must receive information concerning the levels of the controlled variables from sensors in the system. These sensors, or chemoreceptors, are located within the systemic arterial system and within the brain itself. The arterial chemoreceptors, which are often referred to as the
peripheral chemoreceptors, are located in the carotid and aortic bodies; the
central chemoreceptors are located bilaterally near the ventrolateral surface of the medulla in the brainstem. Recent studies have suggested that there may be other central chemoreceptor sites in many places in the brainstem (eg, near the dorsal surface in the vicinities of the NTS and the locus coeruleus).

The peripheral chemoreceptors are exposed to arterial blood; the central chemoreceptors are exposed to cerebrospinal fluid. The central chemoreceptors are therefore on the
brain side of the blood-brain barrier. Both the peripheral and central chemoreceptors respond to increases in the partial pressure of carbon dioxide, although the response may be related to the local increase in hydrogen ion concentration that occurs with elevated

. That is, the sensors may be responding to the increased carbon dioxide concentration, the subsequent increase in hydrogen ion concentration, or both.
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Peripheral Chemoreceptors
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The peripheral chemoreceptors (also called the arterial chemoreceptors) increase their firing rate in response to increased arterial

, decreased arterial

, or decreased arterial pH. There is considerable impulse traffic in the afferent fibers from the arterial chemoreceptors at normal levels of arterial

,

, and pH. The response of the receptors is both rapid enough and sensitive enough that they can relay information concerning breath-to-breath alterations in the composition of the arterial blood to the medullary respiratory center. Recordings made of afferent fiber activity have demonstrated increased impulse traffic in a single fiber to increased

and decreased pH and

, although the sensors themselves may not react to all 3 stimuli. The carotid bodies appear to exert a much greater influence on the respiratory controller than do the aortic bodies, especially with respect to decreased

and pH; the aortic bodies may exert a greater influence on the cardiovascular system. Increased concentrations of potassium ions in the arterial blood can also stimulate the arterial chemoreceptors.
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The response of the arterial chemoreceptors changes nearly linearly with the arterial

over the range of 20 to 60 mm Hg. The exact mechanism by which the chemoreceptors function is uncertain. The carotid body has a complex ultrastructure with type I cells, also called glomus cells; enveloped by type II cells, also called sustentacular cells; and nerve endings. It is not known which cell type is the sensor for changes in

,

, and pH, or if there are different sensors for each of them. Perhaps the type I cells are the sensor for all 3 stimuli or all 3 cell types work together. Some investigators have proposed that increases in hydrogen ion concentration in the arterial chemoreceptors are the primary stimulus to their activity and changes in

and

indirectly stimulate the arterial chemoreceptors by altering the hydrogen ion concentration. Certain drugs and enzyme poisons that block the cytochrome chain or the formation of adenosine triphosphate (ATP) stimulate the carotid body. For example, cyanide can stimulate the carotid body; this may be related to the stimulatory effect of hypoxia on the arterial chemoreceptors. Ganglionic stimulators such as nicotine also stimulate the carotid body.
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Central Chemoreceptors
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The central chemoreceptors are exposed to the cerebrospinal fluid and are not in direct contact with the arterial blood. As shown in Figure 9–8, the cerebrospinal fluid is separated from the arterial blood by the blood-brain barrier. Carbon dioxide can easily diffuse through the blood-brain barrier, but hydrogen ions and bicarbonate ions do not. Because of this, alterations in the arterial

are rapidly transmitted to the cerebrospinal fluid, with a time constant of about 60 seconds. Changes in arterial pH that are not caused by changes in

take much longer to influence the cerebrospinal fluid; in fact, the cerebrospinal fluid may have changes in hydrogen ion concentration
opposite to those seen in the blood in certain circumstances, as will be discussed later in this chapter.
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The composition of the cerebrospinal fluid is considerably different from that of the blood. It is formed mainly in the choroid plexus of the lateral ventricles. Enzymes, including carbonic anhydrase, play a large role in cerebrospinal fluid formation: The cerebrospinal fluid is not merely an ultrafiltrate of the plasma. CSF is continuously produced, mainly in the choroid plexuses, and reabsorbed in the arachnoid villi; it is estimated to turn over 3 to 5 times per day. The pH of the cerebrospinal fluid is normally about 7.32, compared with the pH of 7.40 of arterial blood. The

of the cerebrospinal fluid is about 50 mm Hg—about 10 mm Hg higher than the normal arterial

of 40 mm Hg. The concentration of proteins in the cerebrospinal fluid is only in the range of 15 to 45 mg/100 mL, whereas the concentration of proteins in the
plasma normally ranges from 6.6 to 8.6 g/100 mL. This does not even include the hemoglobin in the erythrocytes. Bicarbonate is therefore the only buffer of consequence in the cerebrospinal fluid, and the buffer line of the cerebrospinal fluid is lower than and not as steep as that of the blood. Arterial hypercapnia will therefore lead to greater changes in cerebrospinal fluid hydrogen ion concentration than it does in the arterial blood. The brain produces carbon dioxide as an end product of metabolism. Brain carbon dioxide levels are higher than those of the arterial blood, which explains the high

of the cerebrospinal fluid.
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The central chemoreceptors respond to local increases in hydrogen ion concentration or

, or both. They do not respond to hypoxia.
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The relative contributions of the peripheral and central chemoreceptors in the ventilatory response to elevated carbon dioxide levels are dependent on the time frame considered. Animals experimentally deprived of the afferent fibers from the arterial chemoreceptors and patients with surgically removed carotid bodies show about 60% to 90% of the normal total steady-state response to elevated inspired carbon dioxide concentrations delivered in hyperoxic gas mixtures, indicating that the peripheral chemoreceptors contribute only 10% to 40% of the steady-state response. Other studies performed on normoxic men indicate that up to one third or one half of the onset of the response can come from the arterial chemoreceptors when rapid changes in arterial

are made. That is, the central chemoreceptors may be mainly responsible for establishing most of the resting ventilatory level or the long-term response to carbon dioxide inhalation, but the peripheral chemoreceptors may be very important in short-term transient responses to carbon dioxide. One author proposed that the arterial chemoreceptors monitor alveolar ventilation by detecting arterial

and pH (and

), whereas the central chemoreceptors monitor the balance of arterial

, cerebral blood flow, and cerebral metabolism by detecting the interstitial pH of the brain. As noted in the section about the peripheral chemoreceptors, many researchers believe that both the arterial and central chemoreceptors respond to hydrogen ion concentration, not

. Of course they are usually very closely related in the body so it is difficult to distinguish their effects.
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Recent investigations have implicated other sensors for carbon dioxide in the body that may influence the control of ventilation. Chemoreceptors within the pulmonary circulation or airways have been proposed but have not as yet been substantiated or localized.