J Appl Physiol 100: 9 –10, 2006;
doi:10.1152/japplphysiol.01097.2005.
Invited Editorial
Why do we have both peripheral and central chemoreceptors?
The peripheral chemoreceptors, the carotid (and aortic) bodies,
detect arterial hypoxemia and stimulate breathing. At normal
arterial PO2 (PaO2) values, they provide a tonic excitatory input
to the brain stem (6), and with hypoxia they respond dramatically as PaO2 falls below 70 Torr. Thus, for oxygen, they
provide an emergency detection system not a breath-by-breath
measure of gas-exchange success.
Both the carotid bodies and the central chemoreceptors
detect changes in CO2/pH and affect breathing. What are their
respective roles and importance? These are old questions (see
Refs. 3, 5, and 7 for historical perspective), but the paper by
Smith et al. (9) in this issue of the Journal of Applied Physiology provides unique data obtained from conscious dogs that
support clear answers to them. The dogs have one carotid body
denervated (the main peripheral chemoreceptor in the dog) and
the other perfused with blood under the control of the investigators. This maintains the tonic input from the carotid body
and avoids any time-related changes that occur in animals after
denervation (6). They induce a near-square-wave increase in
end-tidal PCO2 of 10-12 Torr at 1) both the carotid body and the
central chemoreceptors (“CB ⫹ Central”) or 2) only the central
chemoreceptors (“Central Only”) with the carotid body simultaneously perfused with blood of normal PO2, PCO2, and pH.
There are two protocols: 1) several 1- to 2-min exposures, and
2) 5-min steady-state exposures. The results are remarkable
and clear. With Central Only stimulation, the response (a value
of ventilation ⬎3 SDs above baseline) was delayed by 11.2 s
in the rapid transient protocol, but in the steady-state experiments the response was 63% of that with CB ⫹ CCR stimulation. The carotid bodies provide the rapid response, but the
central chemoreceptors provide most of the steady-state response.
The greater role of the central chemoreceptors in the steadystate response is in good agreement with a large number of
previous studies that used either acute carotid body denervation
or separate perfusion of the two sites in anesthetized animals.
The greater role of the carotid bodies in the rapid response
complements their earlier results linking transient hypocapnia
at the carotid body to hypoventilation and apnea in awake and
sleeping dogs (3). Studies in conscious humans with intact
or surgically resected carotid bodies provide strong support
for this rapid response function of the carotid body.
Fatemian et al. (4) used a multifrequency binary sequence to
force brief CO2 pulses and determine both a fast and slow
time constant for the CO2 response. The fast time constant
was absent in the patients with carotid body resection. That
these two very different approaches, both without the depressant effect of anesthesia, produce the same qualitative
result is powerful evidence that the carotid body is a rapid
arterial CO2 detection system that can monitor the effectiveness of alveolar ventilation.
However, Smith et al. (9) qualify this result, unnecessarily in
my view. They refer to experiments performed in deeply
anesthetized animals with carotid body denervation, surgical
exposure of the ventral medullary surface (the putative central
chemoreceptor site), and measurement of surface pH [see Refs.
1, 9, 18, 22, 33 in Smith et al. (9)]. Here, large step changes in
PCO2 increase fictive breathing (phrenic nerve activity) and
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decrease ventral medullary surface “extracellular fluid” pH
relatively quickly. However, the surgery is drastic, and the
condition of the medullary surface and its blood flow is
questionable [see discussion by Cragg et al. (2)]. Furthermore,
the surface pH response time to a step change in end-tidal CO2
is similar in animals with carotid body denervation [see Refs.
1 and 33 in Smith et al. (9)]. These experiments show that
central chemoreceptors detect pH in interstitial fluid but not in
cerebrospinal fluid. However, in my view, it is unreasonable to
compare response dynamics obtained from experiments of this
nature with those obtained in conscious dogs and humans.
What do central chemoreceptors sense? Some have proposed
that they detect arterial CO2. For example, the proximity of
serotonergic neurons (one putative central chemoreceptor) to
large arteries suggests this view (1). However, the difference in
time for a step change in end-tidal PCO2 to reach the carotid
artery vs. the arteries that supply putative central chemoreceptor neurons should be but a few seconds. If central chemoreceptors detect arterial CO2, then why the large difference in
response times (4, 9)? Perhaps the dynamics of the neural
response to the detected signal differ. Alternatively, the central
chemoreceptors detect a signal other than arterial CO2. There is
strong support for this idea. Pappenheimer and colleagues (5)
used ventriculocisternal perfusion and sustained systemic acidbase changes in chronic unanesthetized goats to correlate
steady-state ventilatory responses with pH values in different
compartments. They concluded that central chemoreceptors
detect brain interstitial fluid pH. In this case, central chemoreceptors are sensitive to changes in arterial PCO2, cerebral blood
flow, and cerebral metabolism. Disturbances in any of these
three entities would change interstitial fluid pH and, thereby,
ventilation. That primary changes in cerebral blood flow can
affect breathing, via central chemoreceptors, independent of
any change in PaCO2 supports this view (see Ref. 10). And, in
conscious animals, the cerebral blood flow response to CO2
will modulate the response dynamics.
Thus the combined recent work of Dempsey, Smith,
Skatrud, and colleagues and older work of Pappenheimer and
colleagues, all in conscious animals, results in a clear picture of
chemoreception. The carotid bodies detect arterial CO2 (and
pH) and monitor alveolar ventilation while the central chemoreceptors detect interstitial fluid pH and monitor the balance of
arterial CO2, cerebral blood flow, and cerebral metabolism.
This balance also provides an indirect index of the balance of
cerebral oxygen delivery and utilization; that is, central chemoreceptors can act as indirect brain tissue oxygen sensors.
This view gives serious purpose to central chemoreceptors and
may explain why they are located at many sites (8). They are
not a mere back-up for the carotid body, which seems perfectly
adequate as a detector of arterial CO2 in physiological
conditions, are especially suited for rapid responses (3, 4, 9),
and provide a needed tonic drive under normal CO2/pH conditions (6).
REFERENCES
1. Bradley SR, Pieribone VA, Wang W, Severson CA, Jacobs RA, and
Richerson GB. Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nat Neurosci 5: 401– 402, 2002.
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Invited Editorial
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PERIPHERAL AND CENTRAL CHEMORECEPTION
2. Cragg P, Patterson L, and Purves MJ. The pH of brain extracellular
fluid in the cat. J Physiol 272: 137–166, 1977.
3. Dempsey JA. Crossing the apnoeic threshold: causes and consequences.
(The Julius H Comroe Lecture). Exp Physiol 90: 13–24, 2004.
4. Fatemian M, Nieuwenhuijs DJF, Teppema LJ, Meinesz S, van der
Mey AGJ, Dahan A, and Robbins PA. The respiratory response to
carbon dioxide in humans with unilateral and bilateral resections of the
carotid bodies. J Physiol 549: 965–973, 2003.
5. Fencl V, Miller TB, and Pappenheimer JR. Studies on the respiratory
response to disturbances of acid-base balance, with deductions concerning
the ionic composition of cerebral interstitial fluid. Am J Physiol 210:
459 – 472, 1966.
6. Forster HV, Pan LG, Lowry TF, Serra A, Wenninger J, and Martino
P. Important role of carotid chemoreceptor afferents in control of breathing in adult and neonatal mammals. Respir Physiol 119: 199 –208, 2000.
7. Loeschcke HH. Central chemosensitivity and the reaction theory.
J Physiol 332: 1–24, 1982.
J Appl Physiol • VOL
8. Nattie EE. Multiple sites for central chemoreception: their roles in
response sensitivity and in sleep and wakefulness (Review). Respir
Physiol 122: 223–235, 2000.
9. Smith CA, Rodman JR, Chenuel BJA, Henderson KS, and Dempsey
JA. Response time and sensitivity of the ventilatory response to CO2 in
unanesthetized intact dogs: central vs. peripheral chemoreceptors. J Appl
Physiol 100: 13–19, 2006.
10. Xie A, Skatrud JB, Khayat R, Dempsey JA, Morgan B, and Russell D.
Cerebrovascular response to carbon dioxide in patients with congestive
heart failure. Am J Respir Crit Care Med 172: 371–378, 2005.
100 • JANUARY 2006 •
Eugene Nattie
Department of Physiology
Dartmouth Medical School
Lebanon, New Hampshire
e-mail: eugene.nattie@dartmouth.edu
www.jap.org