Control Of Breathing I: Chemical Mechanisms
Chemical control of ventilation is mediated via central and peripheral chemoreceptors, which detect arterial Pco2 and pH (central and peripheral) and Po2 (peripheral only), and modulate ventilation via a distributed network of neurones in the brainstem (Chapter 12). Pco2 is the most important factor. The chemoreceptors allow arterial Pco2 and Po2 to be maintained within narrow limits despite large changes in metabolism (e.g. exercise), although ventilation in exercise is also affected by other factors (Chapter 15).
Ventilatory response to changes in
PAco2 and PAo2
Normal alveolar Pco2 (PAco2) is approximately 5.3 kPa (40 mmHg). Increasing PAco2 causes minute ventilation (litres ventilated per minute) to rise in an almost linear fashion (Fig. 11a), by approximately 15-25 L/min for each kPa rise in PAco2 ( 2.7 L/min per mmHg). There is considerable variation between individuals, and athletes and patients with chronic respiratory disease often have a reduced response to PAco2 (Chapters 26 and 44). If PAco2 increases above 10 kPa, ventilation decreases due to direct suppression of central respiratory neurones. A metabolic acidosis (an increase in [H+] caused by reduced
[HC03−]; see Chapter 10) shifts the C02-ventilation response curve to the left, whereas a metabolic alkalosis shifts it to the right (Fig. 11a). Note that a rise in [H+] caused by increased Pco2 is called a respiratory acidosis. Increasing PAo2 from the normal value of approximately 13 kPa (∼100 mmHg) has little effect on the C02-ventilation response curve, but if the PAo2 is reduced, the slope of the relationship becomes steeper and ventilation increases more for any given rise in PAco2 (Fig. 11b). When the effect of PAco2 is investigated independently (at constant PAco2), there is little increase in ventilation until the PAo2 falls below approximately 8 kPa (∼60 mmHg) (Fig. 11c). The effect of reducing PAo2 is however potentiated if the PAco2 is raised - i.e. there is a synergistic (more than additive) relationship between the effects of PAo2 and PAco2.
The central chemoreceptor
The central chemoreceptor consists of a diffuse collection of neurones located near the ventrolateral surface of the medulla, close to the exit of IX and X cranial nerves (Fig. 11d). These are sensitive to the pH of the surrounding cerebrospinal fluid (CSF) and do not respond to Po2. CSF is separated from blood by the blood–brain barrier, a tight endothelial layer lining the blood vessels of the brain. This barrier is impermeable to polar (charged) molecules such as H+ and HC03−, but
C02 can diffuse across it easily. The pH of CSF is therefore determined by the arterial Pco2 and the CSF [HC03−] (Chapter 10), and is not directly affected by changes in blood pH (Fig. 11e). CSF contains little protein, so its buffering capacity is low; therefore, a small change in Pco2 will cause a large change in pH. Stimulation of the central chemoreceptor by a fall in CSF pH (rise in blood Pco2) causes an increase in ventilation. The central chemoreceptor is thought to be responsible for approximately 80% of the response to C02 in humans.
It has a relatively slow response time ( 20 seconds), as C02 has to diffuse across the blood-brain barrier.
The peripheral chemoreceptors
The peripheral chemoreceptors are within the carotid and aortic bodies. The carotid body is a small ( 2 mg) structure located at the bifurcation of the common carotid artery, just above the carotid sinus. It is innervated by the carotid sinus nerve, leading to the glossopharyngeal (Fig. 11f). The aortic bodies are distributed around the aortic arch and are innervated by the vagus. In humans, they are much less important than carotid bodies. The carotid body contains glomus (type I) cells and sheath (type II) cells (Fig. 11g). Glomus cells are responsible for chemoreception; they have dense granules containing neurotransmitters and contact axons of the carotid sinus nerve. The function of sheath cells may be to protect and support the glomus cells, analogous to glial cells in the central nervous system.
Carotid bodies respond to increased Pco2 or [H+] and decreased
Po2 (not blood 02 content) by increasing firin rate in the carotid sinus nerve, and thus ventilation. They have a high blood flow and consequently a small arteriovenous difference for Pco2 and Po2. They respond rapidly (seconds) and are sufficiently fast to detect small oscillations in blood gases associated with breathing. The mechanisms by which changes in Pco2, pH and Po2 are detected are not fully un- derstood, but are believed to involve inhibition of K+ channels in the glomus cell, with consequent depolarization, Ca2+ entry and release of neurotransmitters in the dense granules.
Adaptation: chronic respiratory disease and altitude
When hypercapnia (raised arterial Pco2) is prolonged, for example in chronic respiratory disease, CSF pH gradually returns to normal due to an adaptive and compensatory increase in HC03− transport across the blood-brain barrier. The drive to breathe from the central chemoreceptor is consequently reduced, even though Pco2 is still high. Associated with this, there is occasionally a loss of sensitivity to further increases in Paco2, and the patient's ventilation is then primarily controlled by the level of Po2 (hypoxic drive). Care must be taken with such patients, as giving high concentrations of 02 in order to increase blood 02 saturation may raise the Po2 sufficiently to depress the hypoxic drive and hence ventilation. Normally, approximately 23-28% 02 is given to such patients. This leads to a sufficiently small rise in Pao2 as to have little effect on the hypoxic drive, but because of the steep slope of the 02 dissociation curve (Chapter 8), it can result in a significan improvement in 02 content. At high altitudes, ventilation is stimulated by the low atmospheric Po2. This leads to hypocapnia and alkalosis (as more C02 is blown off), which depress ventilation. 0ver some days, the pH of CSF returns to normal due to HC03− transport out of the CSF, even though the Pco2 remains low, and consequently ventilation increases again. 0ver a longer period, blood pH returns to normal due to renal compensation (Chapter 10). These processes form part of the acclimatization to altitude.