Chemical Control of Respiration

• Excess CO2 or H+ in the blood act directly on the respiratory center in the medulla, greatly increasing the strength of inspiratory and expiratory motor signals.
• A chemosensitive area lies bilaterally beneath the ventral surface of the medulla (in the ventrolateral medulla and retrotrapezoid nucleus), about 0.2 mm deep, highly sensitive to blood PCO2 and H+ concentration. Excitation of these neurons in turn excites the other parts of the respiratory center (dorsal and ventral respiratory groups).
• H+ ions are the actual direct stimulus, but H+ crosses the blood-brain barrier poorly.
• CO2 acts indirectly but powerfully: it diffuses easily across the blood-brain barrier into brain interstitial fluid/CSF, where it combines with water (catalyzed by carbonic anhydrase) to form H2CO3, which dissociates into H+ and HCO3-. The locally generated H+ then stimulates the chemosensitive neurons. Hence, blood CO2 has a far greater effect on stimulating the chemosensitive neurons than does blood H+, because the blood-brain barrier is less permeable to H+.
• This CO2-H+ mechanism is very powerful acutely, but its effect declines over 1-2 days as the kidneys and choroid plexus adjust CSF/blood bicarbonate, restoring H+ toward normal (adaptation).

• Oxygen has little direct effect on the respiratory center itself; instead it acts almost entirely through peripheral chemoreceptors located in the carotid bodies (at the bifurcation of the common carotid arteries) and aortic bodies (along the arch of the aorta).
• These chemoreceptors are richly supplied with blood and contain glandular-like glomus cells that are stimulated by decreased arterial PO2 (particularly below 60-80 mm Hg), and also respond to increased H+ and CO2, though less strongly than the central mechanism.
• Signals from carotid bodies travel via the glossopharyngeal nerve (IX) and from aortic bodies via the vagus nerve (X) to the dorsal respiratory group in the medulla, increasing ventilation.
• This is the only important mechanism for increasing ventilation in response to hypoxia, since a falling PO2 has almost no direct excitatory effect on the medullary respiratory center (in fact prolonged severe hypoxia can even depress it directly).

• Increased PCO2 and H+ and decreased PO2 all stimulate the respiratory center, and their effects are additive, allowing fine regulation of alveolar ventilation to keep arterial PCO2 and pH nearly constant despite changing metabolic demands (e.g., exercise).
• Under normal conditions, CO2/H+ (via the central chemosensitive area) is the dominant moment-to-moment regulator, while the peripheral O2 chemoreceptor mechanism becomes critical during hypoxia (e.g., high altitude, lung disease).

• Guyton and Hall Textbook of Medical Physiology, 4th South Asia Edition, p. 533-535