CENTRAL CHEMORECEPTORS

When CO2-enriched gas is inspired, ventilation increases. The increase in ventilation tends to minimize the rise in PaCO2. Because the amount of CO2 delivered to the chemoreceptors depends on the CO2 carried to them by the arterial blood, the PaCO2 determines the PCO2 in the immediate environment of the chemoreceptors.
The effect of increases in ventilation on PaCO2 can be determined by the following equation:

where 

CO2 is the metabolic production of CO2 each minute, 

A is the alveolar ventilation, PICO2 is the partial pressure of inspired CO2, and K is a proportionality constant.

It can be seen that the greater the increase in ventilation caused by a change in PICO2, the lower is the PaCO2. In conscious humans, central chemoreceptors located within the medulla account for 70%–80% of the increase in ventilation. The peripheral chemoreceptors account for the remainder of the increase in ventilation when CO2-enriched gas is inspired and for all the increase in ventilation produced by hypoxia.

The exact location of the central chemoreceptors is still disputed, although most experimental data indicate that they (1) are distinct from the inspiratory motor neurons themselves, (2) are not located in the dorsal and ventral groups described earlier, and (3) respond to changes in hydrogen ion concentration of brain interstitial fluid but also may respond directly to changes in PCO2 (perhaps through a change in intracellular pH).

Studies in which drugs and temperature probes have been applied to the ventrolateral surface of the medulla have demonstrated abrupt and striking ventilatory effects, suggesting that many of the neurons comprising the central chemoreceptors or their associated axons may be located near the surface. Chemoreceptor activity can be influenced from three different superficial areas (Fig. 4). Recent studies suggest that respiratory cells near the ventral surface are intermingled with cells that also have significant vasomotor effects. Many agents that increase ventilation when applied superficially to the ventral medullary surface (e.g., nicotine, acetylcholine, kainic acid) also raise blood pressure. On the other hand, agents that decrease respiration when similarly applied (e.g., t-amino butyric acid, taurine, enkephalins) also decrease blood pressure. Nonetheless, discrete areas have been described from which either respiratory or vasomotor effects predominate (e.g., the nucleus paragigantocellularis, a collection of cells close to the ventral medulla).

FIG. 4. Ventrolateral medulla and its rostral (R), intermediate (I), and caudal (C) chemosensitive areas.

The crucial experiments in which activity from the central chemoreceptors would be directly recorded have never been performed. Hence, it has been possible to evaluate central chemoreceptor activity only indirectly. This is usually accomplished by measuring the increase in ventilation or phrenic nerve activity produced when the PICO2 is changed. Changes in ventilation theoretically should be related to changes in hydrogen ion concentration in the brain, but this concentration cannot be measured easily, either in humans or in animals. Instead, changes in ventilation are conventionally related to the measured levels of PaCO2. This kind of indirect estimation of central chemoreceptor activity is valid only under restricted circumstances and only if certain assumptions are made. It is assumed, for example, that in a steady state, after CO2 has been inspired for 10 to 20 minutes, changes in PaCO2 reflect changes in the hydrogen ion concentration of the brain. By the Henderson-Hasselbalch equation, hydrogen ion concentration in the brain, as in other tissues, varies according to the ratio PCO2/ HCO–3, where PCO2 is the partial pressure of CO2 at the chemoreceptor in the interstitial fluid and HCO–3 is the bicarbonate concentration of the medullary interstitial fluid. Hence, increases in bicarbonate concentration decrease hydrogen ion concentration, whereas decreases in bicarbonate concentration have the opposite effect.

The relationship between arterial PCO2 and PCO2 in the brain interstitial fluid depends on cerebral venous PCO2 and therefore on cerebral blood flow. The greater the cerebral blood flow, the smaller the difference between PCO2 in arterial blood and in interstitial fluid. As cerebral blood flow increases with PCO2, the change in ventilation produced by a change in PaCO2 depends on the CO2 responsiveness of cerebral blood vessels as well as on the sensitivity of the central chemoreceptors. This may be a significant factor in patients with cerebrovascular disease.

Changes in blood bicarbonate levels are not immediately mirrored in the brain interstitial fluid. In addition, evidence suggests that hydrogen ion concentration in interstitial fluid is actively regulated by cellular pumps at the blood-brain barrier or by the metabolism of brain cells. This means that in metabolic acidosis or alkalosis, neither PaCO2 nor hydrogen ion concentration in blood may reliably indicate the status of hydrogen or bicarbonate ion concentrations in interstitial fluid.

The stimulatory effect of acid injected into the blood on the peripheral chemoreceptors lowers PCO2. Because the transfer of PCO2 between blood and brain interstitial fluid is faster than the transfer of hydrogen or bicarbonate ions, the brain interstitial fluid may actually become alkaline when the blood PCO2 is acutely made acidic. Direct administration of acid into the cerebrospinal fluid to bypass the blood-brain barrier increases the hydrogen ion concentration in brain interstitial fluid and drives the PaCO2 down by stimulating central chemoreceptors.

With chronic acid-base disturbances, hydrogen ion changes in cerebrospinal fluid are usually qualitatively the same as those in the blood but are quantitatively less.

The effect of chronic metabolic acidosis and alkalosis on ventilatory responses to CO2 is shown in Fig. 5. It can be seen that in metabolic acidosis the level of ventilation is greater at any given level of PCO2, whereas in metabolic alkalosis ventilation decreases. These changes in ventilation reflect the altered level of bicarbonate in the brain interstitial fluid. If the same ventilation results are plotted as a function of hydrogen ion concentration in brain interstitial fluid, the response lines are identical.

FIG. 5. Effect of changes in blood bicarbonate on the relationship between ventilation and PCO2. The asterisk indicates the response line at the usual level of HCO–3.

In humans and animals, increases in PCO2 over a wide range cause a virtually linear increase in ventilation. At levels of PaCO2 >80 to 100 mmHg, the response to hypercapnia diminishes and may plateau. Decreases in PaCO2 below the usual level depress ventilation. In anesthetized and sleeping animals and humans, artificial hyperventilation with progressively reduced PCO2 eventually produces apnea. In a normal, awake human, however, active voluntary hyperventilation rarely causes apnea. In most cases, when voluntary hyperventilation is suspended, the increase in ventilation persists for perhaps 30 to 50 seconds. The persistence of ventilation in awake subjects at low levels of PCO2 has been attributed to a “wakefulness drive” caused by the continued impingement of other stimuli (e.g., noise, mechanoreceptor input, and light input) on the respiratory neurons. However, continuation of phrenic nerve activity at low levels of PCO2 has been described even in anesthetized animals made to hyperventilate actively by electrical stimulation of the carotid body nerves. This effect, which has been attributed to persisting reverberations in medullary respiratory neuron circuits, probably contributes to the wakefulness drive and helps stabilize breathing.