"Chemical control of breathing"

There are two main divisions of receptors that measure the chemical composition of blood in order to control the rate and depth of breathing. The peripheral chemoreceptors are those situated outside the CNS. They react mainly to hypoxia and have a very quick reaction time compared to those in the CNS. Those receptors situated in the CNS are called central chemoreceptors. They respond to hypercapnia and react over a much longer time course. They can, however, be responsible for up to 80% of the changes in breathing associated with hypercapnia. And the other 20% of reaction? This is accounted for by a secondary action of the peripheral chemoreceptors.

The peripheral chemoreceptors are situated in the carotid and aortic bodies. The carotid bodies are small, reddish brown structures located posterior to the point of bifurcation of the common carotid arteries. They are innervated by the glossopharyngeal nerves. During development the embryo passes through a fish-like phase. The carotid bodies form in the structures that in the fish would go on to form the gill arches. It is the gills of the fish that sample the surrounding water for its oxygen content.

The carotid bodies are composed of two types of cell. The Type I cells are thought to be the actual sensing cells that release a transmitter to stimulate the sensory nerves. The Type II cells have a greater similarity to the supporting or glial cells of the nervous system.

The aortic bodies are of the same structure as the carotid bodies and are scattered around the arch of the aorta. They send their messages through afferent fibres of the vagal nerve.

Most parts of the body react to hypoxaemia by depression of activity. The peripheral chemoreceptors are, instead, stimulated by hypoxia. It is uncertain how this response is mediated. There is significant evidence for the stimulus to the peripheral receptors being through a build up in metabolites. The chemoreceptors have an exceptionally large blood flow. They are not, therefore, affected by low oxygen content as would occur in anaemia. They are more concerned with testing the .Hence the peripheral chemoreceptors are stimulated by stagnant hypoxia when there is severe circulatory depression.

The peripheral chemoreceptors have a very high metabolic rate and use a large amount of oxygen from the blood supplied to them. Hence it is believed that they are stimulated when there is not a large enough flow of oxygen into the cell to fully breakdown the metabolic products. There is also no agreement yet on the transmitter that is actually used to stimulate the nerves.

What is confirmed, at least experimentally, is the ability of motor nerves to alter the sensitivity of the chemoreceptors by changing the blood flow through them. This reaction to the blood flow through the chemoreceptors allows them also to be activated in cases of hypotension due to haemorrhage.

Alongside stimulation of breathing by the peripheral chemoreceptors they are also responsible for several other reactions. Stimulation of the chemoreceptors causes constriction of peripheral blood vessels (except those under the skin), an increased heart rate and increased activity in the adrenal glands. All of these combine to give a raised blood pressure. This helps maintain an adequate flow of oxygen to vital organs in hypoxic environments.

More important than control of breathing in relation to falls in oxygen levels is the control of breathing in relation to changes in . The majority of response (about 80%) is moderated by the central chemoreceptors. However these react in a time course of minutes. The peripheral chemoreceptors respond to changes in within seconds and provide the initial increase in ventilation rate.

The central chemoreceptors have yet to be identified as specific structures within the brain. They are however been confined to ventrolateral regions of the medulla oblongata as shown in fig 1. They occur about 500m m below the surface of this organ. It is presumed that the nerve endings in these regions react to changes in composition of the interstitial fluid (ISF). There is a complex relationship of ions between the ISF and the CSF. Both of which are regulated by strict control of the movement of ions through the blood-brain barrier. O₂ and CO₂ are, however, freely diffusible across all tissues.

Hence an increase in arterial CO₂ causes rapid diffusion of CO₂ across the blood-brain barrier into the CSF and ISF. There it displaces the reaction to the right producing more H⁺ ions. The drop in pH is probably the specific stimulus to the chemoreceptors. It is also thought that rather than the receptors just testing the pH of the CSF they are responsive to changes in the ISF surrounding them.

A person's sensitivity to changes in CO2 can be visualised by plotting ventilation against . At high levels of carbon dioxide this is an almost linear relationship. At lower pressures there is what is known colloquially as the dog-leg; the degree of ventilation levels out. This shows that there are further afferent controls that keep breathing functioning even when there is no longer any stimulation by the central chemoreceptors. Although there is a certain variation in response to changes in , on average a rise in of about 0.3 kPa (2.5 mmHG) leads to an approximate doubling of minute ventilation. This is providing all other factors remain constant. Should there be a change in arterial pH, then there will be no rise in ventilation rate unless there is an accompanying rise in . This is due to the impermeability of the blood-brain barrier to H⁺ ions. A drop in arterial will also have no effect on the central chemoreceptors although there will be an increased drive to breathe by the action of the peripheral chemoreceptors.

This combination of effect was summed up by Gray in 1945 when he proposed the following formula:

Where VR is the ratio of alveolar ventilation to its rest value. Although the numbers may in some experimental exercises be useful it is more important to note that there are three factors controlling breathing; [H⁺], , and .

These factors interact so that in some instances they provide a braking effect on one another. Consider for example the patient who has gone to a high altitude or place of similarly low . Although there will be a stimulation of breathing by the peripheral chemoreceptors there will come a point where so much CO₂ is being blown off from the blood that the central chemoreceptors are stimulated and depress the breathing so that the subject is not at risk from an alkalosis induced tetany.

(c)1998 Nick Manville