Review of Medical Physiology - William F. Ganong 2002

Respiration
Regulation of Respiration
Chemical Regulation of Respiration

Chemical regulatory mechanisms adjust pulmonary ventilation in such a way that alveolar P_CO2 normally remains constant, the effects of excess Blood H⁺ are mitigated, and P_O2 increases whenever its decline reaches a potentially dangerous level. Minute ventilation is proportional to the metabolic rate; however, The Link Between METABOLISM and Respiration is determined by CO₂ rather than O₂. Receptors in the carotid and aortic bodies are stimulated by an increase in arterial P_CO2 or H⁺ concentration, or by a decrease in P_O2. Following denervation of the carotid chemoreceptors, the response to decreased P_O2 is abolished. The predominant effect of Hypoxia after carotid body denervation is direct depression of the respiratory center. The response to changes in arterial H⁺ concentration within the pH range of 7.3–7.5 is also largely eliminated, although larger changes still exert a partial effect. On the other hand, the response to changes in arterial P_CO2 persists, though it is slower and decreases by no more than 30–35%.

Class="center">Table 36-1. Stimuli Affecting the Respiratory Center

Fig. 36-3. Tracing of two breathing patterns driven by pulmonary stretch receptors: with (A) and without (B) vagal feedback. Note that The rate of increase in phrenic nerve activity driving the Diaphragm is unchanged, but the impulse duration is prolonged in the absence of vagal input.

Carotid and Aortic Bodies

The carotid bodies are located near the carotid bifurcation on each side, and typically two or more aortic bodies are situated near the aortic arch (Fig. 36-4). Each carotid or aortic body (glomus) contains islets of two Cell types: Type I and Type II, surrounded by fenestrated sinusoidal capillaries. Cup-shaped afferent nerve endings lie in close apposition to Type I, or glomus, Cells (Fig. 36-5). Glomus cells resemble the chromaffin cells of The adrenal medulla, containing dense-core vesicles filled with catecholamines that are released in response to hypoxia or cyanide (see below). These cells are stimulated by hypoxia, and the primary emerging neurotransmitter is dopamine, which excites the nerve endings via O₂ receptors. Type II cells are glial-like cells, each enclosing four to six Type I cells. The precise Functions of Type II cells remain unclear.

Outside the capsule of each body, the nerve fibers are myelinated. These fibers have a diameter of 2-5 µm and a conduction velocity of 7-12 m/s. Afferent fibers from the carotid bodies ascend to the Medulla Oblongata via the carotid sinus and glossopharyngeal nerves, whereas fibers from the aortic bodies travel via the vagus nerves. In studies where a single carotid body was isolated and perfused, a graded increase in impulse frequency was observed in active afferent nerve fibers when P_O2 in the perfused blood decreased (Fig. 36-6) or P_CO2 increased.

Fig. 36-4. Location OF THE carotid and aortic bodies

Type I glomus cells possess O₂-sensitive K⁺ channels, in which the open probability decreases in proportion to the severity of hypoxia to which they are exposed. This reduces K⁺ efflux, depolarizes The Cell, and triggers Ca²⁺ influx primarily through L-type Ca²⁺ channels. Ca²⁺ influx initiates Action Potential generation and neurotransmitter release, resulting in the excitation of afferent nerve endings. Pulmonary artery smooth Muscle cells contain similar O₂-sensitive K⁺ channels that initiate hypoxia-induced vasoconstriction (see Chapter 37). This contrasts with systemic Arteries, which contain ATP-dependent K⁺ channels that facilitate greater K⁺ efflux during hypoxia, subsequently leading to vasodilation rather than vasoconstriction. Blood flow through each 2-mg carotid body is approximately 0.04 mL/min, or 2000 mL/100 g of tissue/min, which compares with a blood flow of 54 mL/100 g/min in the Brain and 420 mL/100 g/min in the Kidneys (see Table 32-1). Because tissue blood flow per unit mass is exceptionally high, the cells consume more O₂ than can be supplied by dissolved O₂ alone. Consequently, receptor stimulation does not occur in conditions such as anemia or Carbon monoxide poisoning, where The amount of dissolved oxygen in the blood reaching the receptors is normal, but the total O₂ content bound to Hemoglobin is significantly reduced. Receptor stimulation occurs when arterial P_O2 is low or during vascular stasis, situations where the volume of O₂ delivered to the receptors per minute is diminished. Strong stimulation is also caused by pharmacological agents such as cyanide, which blocks tissue-level O₂ utilization. In sufficient doses, nicotine and lobeline activate chemoreceptors. Furthermore, infusion of K⁺ has been shown to increase the firing rate in afferent chemoreceptor fibers; because plasma K⁺ levels rise during Physical Exercise, this mechanism may contribute to exercise-induced hyperventilation.

Fig. 36-5. Organization OF THE carotid body. Type I (glomus) cells contain catecholamines. Upon exposure to hypoxia, they release these catecholamines, which stimulate cup-shaped nerve fiber endings of the Glossopharyngeal nerve within the carotid sinus. Glomus-supporting Type II glial-like cells surround Type I cells and presumably provide structural and metabolic support.

Fig. 36-6. Changes in the impulse firing rate in a single afferent fiber originating from the carotid body as P_O2 decreases (courtesy of S. Sampson).

Due to their anatomical location, aortic bodies cannot be studied in as much detail as carotid bodies. Their responses are presumably similar, albeit of lesser amplitude. In human subjects whose carotid bodies have been surgically removed while the aortic bodies remain intact, responses are preserved (as is also observed in animals with sequentially denervated carotid and aortic bodies). Such individuals exhibit minor changes in resting pulmonary ventilation, but the ventilatory response to hypoxia is abolished, and the ventilatory responses to CO₂ are reduced by about 30%.

Neuroepithelial bodies, composed of innervated clusters of amine-containing cells, are found in the Airways of both humans and animals. These cells exhibit an outward K⁺ current that decreases during hypoxia, which can trigger cellular depolarization. However, the precise Physiological Role of these hypoxia-sensitive cells remains incompletely understood, given that ablation of the carotid bodies alone virtually abolishes the respiratory response to systemic hypoxia.

Chemoreceptors in the Brainstem

The chemoreceptors responsible for initiating the hyperventilation caused by elevated arterial P_CO2 following denervation of the carotid and aortic bodies reside within the medulla oblongata and are thus referred to as medullary chemoreceptors. They are anatomically distinct from the dorsal and ventral respiratory group Neurons and are localized on the ventral surface of the medulla oblongata (Fig. 36-7).

The monitoring of H⁺ concentration in CEREBROSPINAL FLUID (CSF) and brain interstitial fluid is performed by these chemoreceptors. CO₂ crosses Introduction/36.html">Biological Membranes, such as the blood-brain barrier, rapidly, whereas H⁺ and HCO₃^- diffuse slowly. Upon entering the brain parenchyma and CSF, CO₂ is rapidly hydrated. Subsequent dissociation of H₂CO₃ increases the local H⁺ concentration. In the brain interstitial fluid, H⁺ concentration closely mirrors arterial P_CO2. Experimentally induced changes in CSF P_CO2 have little effect on respiration as long as the H⁺ concentration remains constant, whereas any increase in CSF H⁺ concentration strongly stimulates breathing. This stimulatory effect is proportional to the magnitude of the H⁺ concentration increase. Consequently, the effects of CO₂ on respiration are primarily mediated through its diffusion into the CSF and brain interstitial fluid, where CO₂ raises the H⁺ concentration and stimulates H⁺-sensitive receptors.

Ventilatory Responses to Acid-Base Disturbances

In metabolic acidosis caused, for example, by the accumulation of ketoacidotic products in Diabetes Mellitus, respiratory stimulation occurs (Kussmaul breathing; see Chapter 39). Conversely, in metabolic alkalosis resulting, for example, from prolonged vomiting with loss of HCl, pulmonary ventilation is depressed, causing arterial P_CO2 to rise, which helps restore the H⁺ concentration toward normal (see Chapter 39). If pulmonary hyperventilation occurs independently of an increase in arterial H⁺ concentration, the resulting decrease in P_CO2 lowers the arterial H⁺ concentration below normal (respiratory alkalosis). Conversely, hypoventilation occurring independently of a drop in plasma H⁺ concentration leads to respiratory acidosis.

Fig. 36-7. Rostral (R) and caudal (C) chemosensitive areas on the ventral surface of the medulla oblongata.

Ventilatory Responses to CO₂

Normally, arterial P_CО2 is maintained at approximately 40 mmHg. If tissue metabolism accelerates and increases its level, pulmonary ventilation is stepped up, and pulmonary excretion of СО₂ rises until arterial Р_СО2 returns to normal. This negative feedback mechanism keeps both the production and excretion of СО₂ in precise balance.

When breathing a gas mixture containing СО₂, both alveolar and arterial Р_СО2 rise, and ventilatory stimulation begins as soon as the blood carrying the elevated СО₂ level reaches the medulla oblongata. СО₂ elimination increases, and alveolar Р_СО2 is driven back down toward normal. This explains why relatively large increases in inspired Р_СО2 (e.g., 15 mmHg) cause only a minor rise in alveolar Р_СО2 (e.g., 3 mmHg). Consequently, Р_СО2 is not fully normalized; a new equilibrium is established once alveolar Р_СО2 increases slightly, and hyperventilation persists for as long as the inhalation of СО₂ continues. The true linear relationship between minute ventilation and alveolar Р_СO2 is illustrated in Fig. 36-8. However, this linearity has its limits. When the Р_СО2 of the expired gas mixture approaches alveolar Р_СО2, СО₂ elimination becomes impaired. Furthermore, if the СО₂ content in the inspired gas mixture exceeds 7%, alveolar and arterial Р_СО2 begin to rise sharply despite ongoing hyperventilation. This leads to an accumulation of СО₂ in the body (hypercapnia), which depresses the Central Nervous system—including the respiratory center—and results in headache, restlessness, and ultimately coma (СО₂ narcosis).

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Fig. 36-8. Ventilatory responses of healthy subjects breathing 0₂ and approximately 2, 4, and 6% СО₂. Minute ventilation increases through a combination of increased respiratory rate and tidal volume (reprinted with permission from Lambertsen CJ in: Medical Physiology, 13th ed. Mountcastle VB [editor]. Mosby, 1974).

Ventilatory Responses to Oxygen Deficiency

A decrease in the oxygen content of inspired air triggers an increase in minute ventilation. This stimulatory effect is negligible as long as inspired Р_CО2 remains above 60 mmHg, becoming pronounced only at lower Р_CО2 values (Fig. 36-9). Thus, any reduction in arterial Р_CО2 toward 100 mmHg leads to increased afferent nerve firing from the carotid and aortic chemoreceptors. Two hypotheses attempt to explain why this elevated impulse frequency does not normally increase pulmonary ventilation in healthy individuals until Р_О2 drops below 60 mmHg. Because Hb is a weaker acid than HbО₂ (see Chapter 35), There is a slight increase in arterial H⁺ concentration as Р_О2 decreases and hemoglobin becomes less saturated with О₂. This reduction in H⁺ concentration tends to inhibit respiration. Additionally, any increase in pulmonary ventilation that lowers alveolar Р_СО2 also exerts a depressing effect on breathing. Therefore, the stimulatory effects of hypoxia on pulmonary ventilation are not fully apparent until they become marked enough to overcome these counterbalancing inhibitory influences associated with reduced arterial H⁺ concentration and Р_СО2.

Fig. 36-9. Top: Mean minute ventilation values following exposure to gas mixtures with varying О₂ content. The horizontal line in each case represents the mean value, and the vertical bar denotes one standard deviation. Bottom: Alveolar P_О2 and Р_СО2 values during air breathing at various barometric pressures. The two graphs are aligned so that the О₂ in the inspired gas mixtures (top graph) corresponds to the Р_О2 at different barometric pressures (bottom graph) (data provided by RH Kellogg).

The Effect of a reduction in alveolar Р_O2 on ventilation at a constant alveolar Р_СО2 is shown in Fig. 36-10. When alveolar Р_СО2 is stabilized at 2–3 mmHg above normal, the relationship between pulmonary ventilation and alveolar Р_О2 within the 90–100 mmHg range is reversed. However, at subnormal levels of alveolar P_CО2, hypoxic stimulation of pulmonary ventilation does not occur until alveolar Р_О2 drops to 60 mmHg or lower.

Effect of Hypoxia on the СО₂ Response Curve

In the reverse experiment, when alveolar Р_О2 is held constant, the ventilatory responses to varying amounts of СО₂ follow a linear relationship (Fig. 36-11). When СО₂ response curves are obtained at different Р_О2 levels, the slope of the response curve changes, becoming steeper as alveolar Р_О2 decreases. In other words, hypoxia makes an individual more sensitive to increases in arterial Р_СО2, although the level of alveolar Р_СО2 at which the curves in Fig. 36-11 intersect remains constant. In normal individuals, this threshold value lies below the normal resting alveolar Р_СО2, indicating that there is normally a very small yet perceptible "СО₂ drive" acting on the respiratory center.

Fig. 36-10. Pulmonary ventilation at various alveolar Р_О2 levels with Р_СО2 tightly maintained at 49, 44, or 37 mmHg (data provided by HH Loeschke and KH Gertz).

Effect of H⁺ on the СО₂ Response

The stimulatory effects of H⁺ and СО₂ on respiration interact in much the same way as СО₂ and О₂. In metabolic acidosis, the СО₂ response curve resembles those in Fig. 36-11, except that the curves are shifted to the left. In other words, respiratory stimulation occurs even at lower arterial levels of Р_СО2. It has been calculated that the СО₂ response curve shifts to the left by 0.8 mmHg for each nanomole increase in arterial H⁺ content. More than 40% of the ventilatory response to СО₂ is abolished if the rise in arterial H⁺ generated by СО₂ is prevented. As noted above, the remaining 60% is likely attributable to the direct effect of СО₂ on H⁺ concentration in the cerebrospinal fluid or brain interstitial fluid.

Breath-Holding

Respiration can be voluntarily suspended for a period, though conscious control is ultimately limited and rarely a major factor. The point beyond which breathing can no longer be suppressed is termed the breaking point. It is governed by the rise in arterial Р_СО2 and the fall in Р_О2. Individuals can hold their breath longer following surgical removal of the carotid bodies. Breathing 100% oxygen prior to breath-holding raises alveolar Р_О2, thereby delaying the breaking point. The same holds true after hyperventilating with room air, since СО₂ is blown off and arterial Р_СО2 is initially low. Reflex or mechanical factors also influence the breaking point; thus, subjects who hold their breath to the maximum and then inhale a gas mixture low in О₂ and high in СО₂ can prolong their breath-holding time by an additional 20 seconds or more. Psychological factors play a role as well—individuals who can maintain breath-holding longer while speaking demonstrate better performance than when silent.

Fig. 36-11. Graphical linear family ("fan") of СО₂ responses at various constant levels of alveolar Р_О2.

Hormonal Influences on Respiration

Pulmonary ventilation increases during the luteal phase of the Menstrual cycle as well as during Pregnancy (see Chapter 23). Animal experiments indicate that this is driven by the activation of estrogen-dependent progesterone receptors in the Hypothalamus. However, the exact physiological significance of this increase remains unclear.