The ultimate goal of respiration is to maintain proper concentrations of O2, CO2, and hydrogen ions in the tissues. It is fortunate, therefore, that respiratory activity is highly responsive to changes in each of these substances.
Excess CO2 or excess hydrogen ions in the blood mainly act directly on the respiratory center, causing greatly increased strength of both the inspiratory and the expiratory motor signals to the respiratory muscles.
Oxygen, in contrast, does not have a significant direct effect on the respiratory center of the brain in controlling respiration. Instead, it acts almost entirely on peripheral chemoreceptors located in the carotid and aortic bodies, and these chemoreceptors in turn transmit appropriate nervous signals to the respiratory center for control of respiration.
DIRECT CHEMICAL CONTROL OF RESPIRATORY CENTER ACTIVITY BY CO2 AND HYDROGEN IONS
Chemosensitive Area of the Respiratory Center Be neath the Ventral Surface of the Medulla. We have mainly discussed three areas of the respiratory center: the dorsal respiratory group of neurons, the ventral respiratory group, and the pneumotaxic center. It is believed that none of these is affected directly by changes in blood CO2 concentration or hydrogen ion concentration. Instead, an additional neuronal area, a chemosensitive area, shown in Figure1, is located bilaterally, lying only 0.2 millimeter beneath the ventral surface of the medulla. This area is highly sensitive to changes in either blood PCO2 or hydrogen ion concentration, and it in turn excites the other portions of the respiratory center.
Fig1. Stimulation of the brain stem inspiratory area by signals from the chemosensitive area located bilaterally in the medulla, lying only a fraction of a millimeter beneath the ventral medullary surface. Note also that hydrogen ions stimulate the chemosensitive area, but carbon dioxide in the fluid gives rise to most of the hydrogen ions.
Excitation of the Chemosensitive Neurons by Hydrogen Ions Is Likely the Primary Stimulus
The sensor neurons in the chemosensitive area
are especially excited by hydrogen ions; in fact, it is believed that hydrogen ions may be the only important direct stimulus for these neurons. However, hydrogen ions do not easily cross the blood-brain barrier. For this reason, changes in hydrogen ion concentration in the blood have consider ably less effect in stimulating the chemosensitive neurons than do changes in blood CO2, even though CO2 is believed to stimulate these neurons secondarily by changing the hydrogen ion concentration, as explained in the following section.
CO2 Stimulates the Chemosensitive Area
Although CO2 has little direct effect in stimulating the neurons in the chemosensitive area, it does have a potent indirect effect. It has this effect by reacting with the water of the tissues to form carbonic acid, which dissociates into hydrogen and bicarbonate ions; the hydrogen ions then have a potent direct stimulatory effect on respiration. These reactions are shown in Figure1.
Why does blood CO2 have a more potent effect in stimulating the chemosensitive neurons than do blood hydrogen ions? The answer is that the blood-brain barrier is not very permeable to hydrogen ions, but CO2 passes through this barrier almost as if the barrier did not exist. Consequently, whenever the blood PCO2 increases, so does the PCO2 of both the interstitial fluid of the medulla and the cerebrospinal fluid. In both these fluids, the CO2 immediately reacts with the water to form new hydrogen ions. Thus, paradoxically, more hydrogen ions are released into the respiratory chemosensitive sensory area of the medulla when the blood CO2 con centration increases than when the blood hydrogen ion concentration increases. For this reason, respiratory center activity is increased very strongly by changes in blood CO2, a fact that we subsequently discuss quantitatively.
Decreased Stimulatory Effect of CO2 After the First 1 to 2 Days. Excitation of the respiratory center by CO2 is great the first few hours after the blood CO2 first increases, but then it gradually declines over the next 1 to 2 days, decreasing to about one fifth the initial effect. Part of this decline results from renal readjustment of the hydrogen ion concentration in the circulating blood back toward normal after the CO2 first increases the hydrogen concentration. The kidneys achieve this readjustment by increasing the blood bicarbonate, which binds with the hydrogen ions in the blood and cerebrospinal fluid to reduce their concentrations. But even more important, over a period of hours, the bicarbonate ions also slowly diffuse through the blood-brain and blood–cerebrospinal fluid barriers and combine directly with the hydrogen ions adjacent to the respiratory neurons as well, thus reducing the hydro gen ions back to near normal. A change in blood CO2 concentration therefore has a potent acute effect on con trolling respiratory drive but only a weak chronic effect after a few days’ adaptation.
Quantitative Effects of Blood PCO2 and Hydrogen Ion Concentration on Alveolar Ventilation
Figure 2 shows quantitatively the approximate effects of blood PCO2 and blood pH (which is an inverse logarithmic measure of hydrogen ion concentration) on alveolar ventilation. Note especially the marked increase in ventilation caused by an increase in PCO2 in the normal range between 35 and 75 mm Hg, which demonstrates the tremendous effect that CO2 changes have in controlling respiration. By contrast, the change in respiration in the normal blood pH range, which is between 7.3 and 7.5, is less than one tenth as great.
Fig2. Effects of increased arterial blood PCO2 and decreased arterial pH (increased hydrogen ion concentration) on the rate of alveolar ventilation.
Changes in O2 Have Little Direct Effect on Control of the Respiratory Center
Changes in O2 concentration have virtually no direct effect on the respiratory center itself to alter respiratory drive (although O2 changes do have an indirect effect, acting through the peripheral chemoreceptors, as explained in the next section).
We learned in Chapter 41 that the hemoglobin-oxygen buffer system delivers almost exactly normal amounts of O2 to the tissues even when the pulmonary PO2 changes from a value as low as 60 mm Hg up to a value as high as 1000 mm Hg. Therefore, except under special conditions, adequate delivery of O2 can occur despite changes in lung ventilation ranging from slightly below one-half normal to as high as 20 or more times normal. This is not true for CO2 because both the blood and tissue PCO2 change inversely with the rate of pulmonary ventilation; thus, the processes of animal evolution have made CO2 the major controller of respiration, not O2.
Yet for those special conditions in which the tissues get into trouble for lack of O2, the body has a special mechanism for respiratory control located in the peripheral chemoreceptors, outside the brain respiratory center; this mechanism responds when the blood O2 falls too low, mainly below a PO2 of 70 mm Hg, as explained in the next section.
