chemoreceptor

chemoreceptor Take a deep breath in and hold it. Breath-hold times can range from as little as a few seconds to a much more heroic several minutes — but what limits these times? Certainly a number of factors, including motivation and the volume to which the lung was inflated, are important, but the actual ‘break-point’, defined as the time from the beginning of the breath-hold to the point at which the overwhelming urge to breathe can no longer be resisted, is ultimately determined by the carbon dioxide (CO₂) and oxygen (O₂) levels in arterial blood. These levels are expressed as the partial pressure (P) of each gas with which the blood would be in equilibrium. They rise and fall respectively throughout a breath-hold (as we continue to metabolize foodstuffs for energy) and the break-point is reached when the Pco₂ in arterial blood has risen from its normal value of around 40 mmHg (5.3 kPa) to around 50 mmHg (6.7 kPa) and the Po₂ has fallen from its normal value of around 95 mmHg (12.6 kPa) to around 70 mmHg (9.3 kPa). Breath-hold times can therefore be increased by prior hyperventilation (which lowers the initial carbon dioxide) or by breathing pure oxygen instead of air. Combining these two methods will maximally — and dramatically — increase breath-hold times. OK: breathe out, now!

As breath-hold times are ultimately determined by the concentration of gases in the blood, it follows that sensors must exist which can ‘taste’ the chemical composition of blood. These sensors are known as chemoreceptors, and they play a crucial role in acid–base homeostasis and oxygen supply. They help to maintain the appropriate oxygen, carbon dioxide, and pH in the body by initiating a variety of cardiovascular and respiratory reflexes. Such reflexes are required not just during breath-holds but whenever these levels are altered by changes in metabolism, changes in environment, or disease — for example during exercise, at high altitude, or during respiratory failure caused by lung disease.

Chemoreception occurs both in the brain and in the blood vessels. Sensitivity to brain CO₂ and pH is known to exist in the brain stem — ‘tasting’ the fluid environment of the neurons where correct pH is crucial to function. Any change in blood carbon dioxide is transmitted to the brain: here, as elsewhere, a rise in carbon dioxide increases acidity; the response of the central chemoreceptor mechanism to such a rise is to stimulate breathing, thus tending to correct the change by the loss of more carbon dioxide. Specific structures mediating these ‘central chemoreceptor’ responses have not yet however been identified with certainty. In contrast, chemosensitivity to changes in the blood was localized in the 1920s to specialized ‘peripheral chemoreceptors’. The most functionally significant group of these receptors is found within the carotid bodies, located bilaterally in the neck close to the carotid artery: there are others in the ‘aortic bodies’ around the origin of the aorta.

The first descriptions of a small structure, only 5–8 mm long and weighing just a few mg, lying beside the division of the carotid artery in the neck, appeared during the eighteenth century. At first called a ‘ganglion’, it was later thought to be a gland. It was not until 1927 that Fernando de Castro, an anatomist working in the Cajal Institute in Madrid, recognized the carotid body as a sensory organ and postulated its function as a chemoreceptor with afferent nerves to the brain. The sensory function of the carotid (and aortic) chemoreceptors was confirmed by a series of physiological studies performed around the same time by Jean-Frans Heymans and his son, Corneille, in Ghent, Belgium, for which Corneille received the Nobel prize in 1938. By then it had been established that these receptors were stimulated by high carbon dioxide and/or low oxygen in the blood, causing a reflex increase in breathing and in blood pressure. Shortly after these discoveries, a series of studies initiated in Japan and continued in the US described how bilateral division of the afferent nerves from the carotid bodies brought relief in a number of sufferers from asthma. Unfortunately, these results could not be confirmed, and a possible mortality attributable to the surgical intervention led to the banning of the procedure. Studies following such procedures did however provide evidence that people without carotid body function did not show the normal increase in breathing in response to low oxygen.

The carotid body is highly vascular and receives the highest blood flow, relative to its size, of any organ in the body. It is divided into a number of lobules, each containing clusters of two distinct cell types together with arteriolar blood vessels and capillaries, nerve fibres, and a few autonomic ganglion cells. Type I cells, of which there are tens of thousands in each carotid body, are believed to be the primary transducer elements. A smaller number of Type II cells envelop them and provide a supportive function, like that of glia in the nervous system. In the Type I cells there are numerous vesicles containing catecholamines; they also store other substances, including acetylcholine, certain neuropeptides, and nucleotides as well as the enzymes required to produce the ‘messenger’ gases, nitric oxide and carbon monoxide. Because these features resemble those of the terminal of a nerve fibre, the Type I cell is believed to form the equivalent of a nerve-to-nerve synapse with the sensory nerve endings close to it, generating action potentials in them by the graded release of a transmitter. In common with almost all synapses, the release of neurotransmitter is dependent upon an elevation in the concentration of ionic calcium within the Type I cell.

Peripheral chemoreceptors share with central chemoreceptors a responsiveness to acidity and carbon dioxide, but their uniqueness lies in their ability also to sense lowered oxygen (hypoxia) in arterial blood. The most likely neurotransmitter released during hypoxia is dopamine, with the other chemicals stored in the Type I cell acting as modulators. (This dopamine-secreting action of Type I cells has led to the recent trial use of surgical autografts of carotid body tissue in the treatment of animal models of Parkinson's disease.) In common with almost all synapses, the release of neurotransmitter is dependent upon an elevation in the concentration of ionic calcium (Ca²⁺) within the Type I cell; evidence suggests that Ca²⁺ ions enter the Type I cell through voltage-gated channels, opened when the cell is depolarized in response to hypoxia or other stimuli. The depolarization of the cell occurs by the closure of oxygen-sensitive potassium ion channels in the cell membrane. The precise nature of the potassium channel and the mechanism by which it senses the stimulus is not yet known.

At the carotid body, stimuli are thus translated into sensory action potentials that are graded in intensity with the degree of stimulation. Carotid body sensory discharge increases exponentially with increasing hypoxia and linearly with carbon dioxide, and if the two stimuli are applied together the response is greater than the sum of the two responses to each stimulus independently. This means that the receptors are exquisitely sensitive to the combined rise in carbon dioxide and fall in oxygen which occurs in breath-holding, and they act rapidly to cause deeper breaths after even minor interruptions of breathing such as during speech or singing. These breath-by-breath adjustments constitute the role of the peripheral chemoreceptors in a normal environment during everyday activity, and they also implement the rapid increase in breathing at the start of exercise. Their responsiveness to hypoxia causes the increase in breathing that is common experience at high altitude, allowing the concentration of oxygen reaching the lungs to be higher than it would be without such a response. In hypoxia also, they initiate vasoconstrictive reflexes which act to maintain the arterial blood pressure. Their response to acidaemia — a fall in the pH of the blood — causes increased breathing, and thus tends to correct the acidity by the loss of more carbon dioxide from the lungs.

In summary; the peripheral chemoreceptors perform a vital function in the maintenance of O₂ and CO₂ levels in arterial blood, and of acid– base balance, by translating blood-borne chemical stimuli into electrical activity in afferent nerves, leading to homeostatic respiratory and cardiovascular reflexes.

Prem Kumar

See also altitude; breathing; hypoxia; neurotransmitters.