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J Appl Physiol 88: 1489-1495, 2000;
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Vol. 88, Issue 4, 1489-1495, April 2000

HIGHLIGHTED TOPICS
Single-unit recordings of arterial chemoreceptors from mouse petrosal ganglia in vitro

David F. Donnelly1 and Ricardo Rigual2

1 Division of Respiratory Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520; and 2 Department of Biochemistry and Molecular Biology and Physiology, Institute of Biology and Molecular Genetics, Universidad de Valladolid, Consejo Superior de Investigaciones Cientificas, 47005 Valladolid, Spain


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

A preparation was developed that allows for the recording of single-unit chemoreceptor activity from mouse carotid body in vitro. An anesthetized mouse was decapitated, and each carotid body was harvested, along with the sinus nerve, glossopharyngeal nerve, and petrosal ganglia. After exposure to collagenase/trypsin, the cleaned complex was transferred to a recording chamber where it was superfused with oxygenated saline. The ganglia was searched for evoked or spontaneous unit activity by using a glass suction electrode. Single-unit action potentials were 57 ± 10 (SE) (n = 16) standard deviations above the recording noise, and spontaneous spikes were generated as a random process. Decreasing superfusate PO2 to near 20 Torr caused an increase in spiking activity from 1.3 ± 0.4 to 14.1 ± 1.9 Hz (n = 16). The use of mice for chemoreceptor studies may be advantageous because targeted gene deletions are well developed in the mouse model and may be useful in addressing unresolved questions regarding the mechanism of chemotransduction.

carotid body chemoreceptor; knockout; hypoxia


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

CAROTID BODY CHEMORECEPTORS transduce a decrease in arterial oxygen tension into an increase in spiking activity on some carotid sinus nerve afferent fibers. The mechanism of transduction has remained enigmatic but is presumably dependent on the release of an excitatory transmitter from the glomus cells, a secretory cell apposed to the afferent nerve ending. However, the mechanism of oxygen sensing and identification of the purported transmitters have been problematic, because, in general, applications of antagonists to purported transmitters or oxygen sensors have produced variable and inconsistent results (16). The use of mice with targeted gene disruptions may offer an alternative approach to pharmacological interventions and give better specificity. Indeed, these mice have been used in the study of ventilatory changes during hypoxia or hyperoxia (18). However, ventilatory measurements are indirect, and the use of mice to understand transduction better is dependent on our ability to access chemoreceptor function directly.

In 1982, Biscoe and Pallot (4) undertook the first recordings of mouse chemoreceptors in normal and wobbler-mutant mice using a wire recording of the sinus nerve in vivo. Because of the small size of the sinus nerve, these recordings were technically difficult, unstable, and generally had multiple modalities. Furthermore, the small size of the sinus nerve obviated an ability to further dissect the nerve to obtain better resolution of unit activity or modal specificity.

The present work was undertaken to develop a model by which high-resolution, single-unit chemoreceptor recordings may be undertaken from mouse chemoreceptors in vitro. Here we report a modification of a technique that our laboratory has previously employed to record rat chemoreceptors in vitro (8). For this, the carotid body is harvested along with the petrosal ganglia, and extracellular recordings are obtained by using electrodes placed in the petrosal ganglia. Initial experiments demonstrated good stability and exceptional signal-to-noise ratio (signal/noise) compared with other recording methods.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Initial carotid body isolation. Mice (6-8w, wild type, CD-1; Charles River) were deeply anesthetized by placement in a closed chamber with an atmosphere that was saturated with methoxyfluorane vapor. After deep anesthesia, as evidenced by an absence of motor movements (outside of breathing) and an absence of withdrawal reflex, the mice were removed and decapitated. The carotid body and petrosal ganglia were harvested under a dissecting microscope with the use of the following approach. During the following procedure, the exposed area was washed with cold saline to prevent desiccation.

1) The carotid arteries were dissected free and laterally retracted, allowing exposure of the carotid bifurcation and nodose ganglia.

2) The superior cervical ganglia was gently pulled free with fine forceps (Dumont no. 5) and cut free of the bifurcation.

3) The bone caudal to the entry point of the hypoglossal nerve was cut with a sharp scalpel blade (no. 10), and the bone was gently pried apart to allow for better access to the nodose/petrosal ganglia.

4) The internal carotid artery was cut at the point of its secondary bifurcation.

5) The vagus nerve next to the cut common carotid artery was dissected free to the nodose ganglia. The pharyngeal branch of the vagus was cut at its junction with the main branch of the vagus.

6) By gently pulling on the vagus nerve, the glossopharyngeal nerve and petrosal ganglia were dissected free of the surrounding tissue. After cutting centrally to the petrosal ganglia, the ganglia and glossopharyngeal nerve were reflected over the carotid bifurcation.

7) By gently pulling on the common carotid artery, the carotid bifurcation and glossopharyngeal nerve with attached ganglia were pulled away from the surrounding tissue and cut free. The bifurcation was placed in cold, oxygenated (95% O2-5% CO2) saline (in mM: 120 NaCl, 3 KCl, 2 CaCl2, 1 Na2HPO4, 1 MgSO4, 24 NaHCO3, and 10 glucose).

8) By using sharp dissection, any muscle tissue was removed, and the common carotid and external carotid arteries were dissected free. The remaining portion of the bifurcation and glossopharyngeal nerve was placed in a 35-mm culture dish filled with dilute solutions of collagenase (0.01%, type P; Boeheringer) and protease (0.005%, type IX; Sigma Chemical) dissolved in oxygenated saline at room temperature for 30 min. The dish was gently rocked on a shaker table.

9) At the end of the enzyme exposure, the chemoreceptor complex was transferred to fresh oxygenated saline. The remaining connective tissue was gently trimmed from around the carotid body. In this case, it is often easier to identify the sinus nerve as the first nerve to exit from the glossopharyngeal nerve and clean the sinus nerve toward the carotid body.

10) The cleaning step was the most difficult because the sinus nerve is quite small and fragile (~20-µm diameter) and up to 1 mm in length (Fig. 1). Transfer of the chemoreceptor complex is by aspiration into a large-bored pipette with care taken to minimize pulling the carotid body with the sinus nerve.


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  		Fig. 1.   Low-power photomicrograph (magnification ×55) of the chemoreceptor complex after harvesting and cleaning. Shown are carotid body, sinus nerve, glossopharyngeal nerve, and petrosal ganglia. Note that the sinus nerve is relatively long (~1 mm) and thin (~20 µm), thus requiring considerable care to avoid damage to nerve fibers during transport or superfusion.

Nerve recording and unit identification. The chemoreceptor complex was transferred to a recording chamber (volume approx 250 µl) placed on an inverted microscope and superfused at 2.5 ml/min with heated (32-33°C) saline equilibrated with 20 or 95% O2-5% CO2-balance N2. The lower temperature (compared with body temperature) was selected because viability may be prolonged at the lower temperature and transduction of hypoxic stimuli still occurs (17). A metal microelectrode (10 MOmega ; Frederick Haer, Brunswick, ME) was advanced into the carotid body, which held the carotid body in place as well as provided a means of initiating an orthodromic action potential. A second microelectrode was advanced into the petrosal ganglia and used to hold the ganglia in place in the perfusion chamber.

Unit activity was recorded by using a glass suction electrode advanced into the ganglia. Electrode tip size was ~30 µm in diameter, and the electrode was filled by aspirating chamber saline into the electrode barrel. Because basal chemoreceptor spiking rates are slow, a cathodal electrical stimulus (100-500 µA, 0.5-ms duration) was delivered by a constant-current source (BSI-2, BAK Instruments, Rockville, MD) to evoke a spike with high probability within the display window of an oscilloscope sweep. Once detected from the electrical stimulus, unit activity was tested for spontaneous action potential generation. Only then was it tentatively identified as arising from chemoreceptor afferent fibers. The search area was primarily concentrated near the entry point of the glossopharyngeal nerve fibers into the ganglia, which is the point of highest chemoreceptor somal concentration in the rat (13).

Experimental protocol. Once a purported chemoreceptor unit was observed based on orthodromic electrical activation, the electrical stimulus was removed, and spontaneous unit activity was measured. The response to acute hypoxia was tested by switching the perfusate from normoxia to saline equilibrated with 5% CO2-balance N2 for 2 min. Without an oxygen scavenger, chamber PO2 fell over a period of ~1 min and reached a nadir of ~20 Torr.

Data analysis. The time period between an orthodromic electrical stimuli and arrival of the orthodromic spike was digitized (pCLAMP, Axon Instruments, Foster City, CA) and measured to give an estimate of the conduction velocity based on the latency between the stimulus artifact and arrival of the orthodromic action potential. Signal/noise was calculated based on the ratio of the peak voltage change from baseline during the action potential to the standard deviation of the resistive noise recorded in the absence of spikes. In some cases, samples of nerve activity during normoxia and during hypoxia were digitized at 6 kHz and recorded to disk (Axotape, Axon Instruments).

Spontaneous spiking activity was converted to logic pulses by a window discriminator (DIS-1, BAK Instruments) and summed each second (TECMAR Labmaster, Scientific Solutions). Baseline spontaneous spiking activity was measured over 100 s during superfusion with normoxic saline (PO2 approx  150 Torr) and during the peak discharge over 3 s during hypoxic stimulation (PO2 approx  20 Torr).

In some cases, the time period between neighboring spikes was timed to 1-ms accuracy and measured for ~1,000 consecutive spikes. A subgroup of 500 consecutive intervals was selected on the basis of a steady-state mean discharge frequency and used to construct an interval histogram. Counts in the histogram bins were compared with those expected for a random, Poisson-type process by using a chi 2 statistic, as previously described (5, 22).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Evoked activity and signal/noise. Identification of purported chemoreceptor afferent cells was undertaken by applying a brief electrical stimulus (100-500 µA, 0.5-ms duration) through a stimulating electrode placed in the carotid body. Evoked orthodromic activity was recorded by using a suction electrode placed in the petrosal ganglia. An example of the evoked action potential is shown in Fig. 2 in which the stimulus artifact is followed by an orthodromic spike.


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  		Fig. 2.   Evoked action potential after an electrical stimulus to the carotid body. Voltage on the recording (suction) pipette vs. time is shown. A constant-current cathodal stimulus (100 µA, 0.5-ms duration) was delivered through a metal electrode placed within the carotid body, and this was followed by an orthodromic spike at 3.2-ms latency. Root-mean-square (RMS) noise in absence of action potentials was measured over 5 ms in the postspike period. Action potential deflection, in this case, was 44 standard deviations above the recording noise.

Figure 2 also illustrates the relative signal/noise of the ganglion recording technique for these afferent fibers. The recording noise in the absence of spiking activity was measured as the variance over a 5-ms period (0.12 unit) and compared with the peak voltage change of the evoked spike (5.3 units). The relative spike signal was 5.3/0.12 = 44 standard deviations above the noise. Average signal/noise for the 16-unit recordings was 57 ± 10 standard deviations.

The latency between the stimulus artifact and evoked spike may be useful for calculation of the conduction velocity and identification of fiber type. For example, in Fig. 2 the conduction time was 3.5 ms, and for the population the conduction time was 3.06 ± 0.15 ms (n = 16). Although the conduction distance was not accurately measured in these preparations, it is ~1.5 mm (Fig. 1), resulting in an estimated conduction velocity for the sample of 0.5 m/s.

Spiking activity during normoxia and hypoxia. All 16 purported chemoreceptor afferents had spontaneous spiking activity during normoxia (Fig. 3). On average, spiking activity in normoxia was 1.3 ± 0.4 Hz. After the perfusate was switched to saline equilibrated with 5% CO2-balance N2, chamber PO2 fell to near 20 Torr over the course of 60-80 s (Fig. 3). Peak, single-fiber spiking activity in hypoxia was 14.1 ± 1.9 Hz (n = 16). The relationship between chamber PO2 and spiking activity showed the typical exponential relationship (Fig. 4). Chamber PO2 at which the nerve activity increased to one-half of the peak level was 45 ± 4 Torr (n = 14).


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  		Fig. 3.   Mouse chemoreceptor discharge activity during normoxia and hypoxia. PO2 (top) and chemoreceptor unit (middle) activity vs. time are shown. Perfusate was switched from saline equilibrated with 20% O2-5% CO2-balance N2 to saline equilibrated with 5% CO2-balance N2. Some oxygen was added to the saline from diffusion through the perfusion tube and diffusion within the open perfusion chamber. Note increase in spike activity from ~1 Hz to a peak of 20 Hz during hypoxia. Inset: oscillographic sweep (10-ms duration) triggered from an electrical stimulus (100 µA) delivered to the carotid body. Note evoked unit spike following the stimulus artifact. Bottom: polygraphic tracings of extracellular unit activity during normoxia (arrow on left) and hypoxia (arrow on right).



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  		Fig. 4.   Mouse chemoreceptor activity vs. perfusate PO2. Each data point is instantaneous superfusate PO2 and unit spiking activity with the relationship fit to a single exponent. Decrease in chamber PO2 to evoke a half-maximal increase in nerve activity was ~40 Torr.

Pattern of afferent spiking activity from mouse chemoreceptors. In four cases, the interspike interval periods were timed to 1-ms accuracy and used to calculate interspike-interval histograms and serial correlation coefficients. In these four cases, a subsample of 500 consecutive intervals was selected based on a constant average discharge frequency. In all four cases, the interspike-interval histogram was not significantly different from exponential (Fig. 5), suggesting that the pattern generator was not significantly different from a Poisson-type random process.


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  		Fig. 5.   Analysis of interspike interval periods for mouse chemoreceptor activity. Top: unit firing rate per 5 s vs. time. A sample of 500 consecutive interspike intervals was selected based on a relatively constant discharge frequency. Inset: oscillographic sweep of 7 spontaneous action potentials as triggered by the unit acceptance pulse. Bottom: interspike interval histogram for 500 interspike intervals. The histogram was not significantly different from a single exponent (dotted line), suggesting that the generation process was random.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present results demonstrate the feasibility of recording single-unit chemoreceptor activity with high signal/noise from the mouse carotid body and provide preliminary observations showing that spike generation in mouse chemoreceptors is similar to that of other species. The "chemoreceptor complex" preparation (carotid body, sinus nerve, glossopharyngeal nerve, petrosal ganglia) offers significant advantages over conventional nerve recording with excellent stability and high signal/noise.

Experimental preparation. This experimental preparation is similar to that which our laboratory originally developed for rat ganglion recordings of chemoreceptor afferent fibers (8). This, in turn, was a variation of that originally developed by Belmonte and colleagues (3) for intracellular recordings of cat petrosal neurons with carotid body projections. In both cases, the carotid bodies were harvested along with the petrosal ganglia and maintained in vitro. In our model, we used glass suction electrodes to obtain extracellular unit activity from the soma of the petrosal neurons. This was based on the previous success of Vidruk and Dempsey (25) and Mulligan et al. (20), who used tungsten microelectrodes to obtain extracellular unit recordings from petrosal neurons of pig and cat in vivo.

Harvesting of the petrosal ganglia along with the carotid body offers several advantages. First and foremost, it allows single-unit discrimination that is far beyond that obtained by using nerve recordings and allows for quantifying chemoreceptor activity based at a single unit level. Multiunit activity, as is generally recorded from the whole or partial sinus nerve, gives no information regarding the magnitude of fiber recruitment, magnitude of contamination due to recording noise, or magnitude of nonchemoreceptor spiking. These problems may be especially difficult to avoid in the mouse, because the nerve is too small to allow for dissection into smaller strands (4). The improved signal/noise of the somal recording compared with the axon recording may be readily appreciated by comparing the oscillographic traces of Figs. 2, 3, and 5 to previous recordings by our laboratory (17) and others (24) from rat sinus nerve. The improvement in signal/noise is due to not only the greater electrical field around the soma of afferent neurons (because of their larger size) but also the physical separation from the field of other chemoreceptor afferents. Background spiking activity from neighboring somas was generally not observed in our recordings (Figs. 3 and 5).

Mouse chemoreceptor discharge characteristics. All of the discharge characteristics from the mouse are consistent with those reported previously for the rat and are generally consistent with those obtained in larger species (cat, dog, pig, goat). Baseline spiking activity was ~1 Hz, and peak rates were ~14 Hz in the mouse. Similar baseline and peak rates were previously recorded in the rat under similar conditions, but the peak rate in the rat was slightly higher, perhaps because of the use of an oxygen scavenger in the previous rat studies (7, 17). The increase in spiking activity occurred primarily at <80-Torr PO2, compared with ~150 Torr in the rat (24). However, this is to be expected because the rat carotid body is larger (increasing the diffusion gradient) and the previous experiments were done at a higher temperature.

The spike generation property of mouse chemoreceptors is also consistent with that of other species. The interspike interval distribution was exponential, suggesting that the generation process was random, i.e., like the process of radioactive decay. A similar result was previously obtained from the analysis of afferent spike generation of rat chemoreceptors in vitro (5) and one single-fiber recording of mouse chemoreceptors in vivo (4). In other species, interspike intervals also approximate a random process having a mean frequency that is modulated by the respiratory and cardiac cycles (15). Of course, this modulation would be absent in vitro. In addition, some chemoreceptors, particularly in birds and goats, produce doublet spikes, which are manifest as a large number of counts in the first time bin of the interval histogram (21, 23). However, doublet bursting was not observed in our mouse recordings.

Potential usefulness for enhanced understanding of the chemotransduction process. The mechanism by which the afferent spike is initiated at the afferent nerve terminal is presently unknown. Whereas it is widely assumed that an excitatory transmitter is involved, the identity and nature of the presumed chemical are unresolved. Whereas a complete assessment of the purported transmitters is beyond the present scope, the example of dopamine may illustrate the point. Dopamine is synthesized and stored by the glomus cell and is released by hypoxia in close temporal association with the increase in afferent nerve activity (6, 12). Furthermore, the messages for dopamine D1 and D2 receptors are expressed in both the carotid body and petrosal ganglia (1, 2, 14). This has been taken to argue that dopamine may serve an excitatory role, but other observations are seemingly inconsistent with this role. In particular, exogenous administration of dopamine generally inhibits ongoing nerve activity, and administration of dopamine antagonists increases afferent nerve activity (9, 19, 26). One may conclude either that catecholamine secretion is not causal to the increase in afferent nerve activity or that other dopamine receptors (e.g., autoreceptors) are the primary target for exogenous agonists and antagonists.

The use of genetically altered mice perhaps offers the optimal approach to resolve such issues. A pharmacological approach has an uncertainty of whether the agonist or antagonist reaches the desired site. In contrast, mice with specific targeted disruptions of dopamine D1, D2, D3, and D4 receptors have all been developed and can be maintained to adulthood (10). A direct assessment of chemoreceptor responsiveness in these mice might yield a unique insight into the role(s) of dopamine in chemoreceptor transduction. In a similar vein, the use of knockout animals has already been used to assess the role of neurokinin type 1 receptors (11) and neuronal nitric oxide synthase (18) in the ventilatory responses to hypoxia. A natural extension of these experiments would be an examination of the consequences of these knockouts on peripheral chemoreceptor function.

In summary, the present report details a method of harvesting and obtaining single-unit chemoreceptor afferent recording in mouse carotid body in vitro. The results show spontaneous spiking rates during normoxia and hypoxia and a pattern of spike generation that is generally consistent with that obtained in rat carotid body in vitro and cat carotid body in vivo. It is hoped that the application of this model will ultimately prove useful for better understanding the mechanism of chemotransduction.


    ACKNOWLEDGEMENTS

The intellectual guidance and support of Constancio Gonzalez is gratefully acknowledged.


    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-46149.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Original submission in response to a special call for papers on "Hypoxia Influence on Gene Expression."

Address for reprint requests and other correspondence: D. F. Donnelly, Dept. of Pediatrics, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520 (E-mail: David.Donnelly{at}Yale.edu).

Received 27 July 1999; accepted in final form 5 November 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Bairam, A., Frenette J., Dauphin C., Carroll J. L., and Khandjian E. W. Expression of dopamine D1-receptor mRNA in the carotid body of adult rabbits, cats and rats. Neurosci. Res. 31: 147-154, 1998[ISI][Medline].

2.   Bairam, A., and Khandjian E. W. Expression of dopamine D2 receptor mRNA isoforms in the carotid body of rat, cat and rabbit. Brain Res. 760: 287-289, 1997[ISI][Medline].

3.   Belmonte, C., Gallego R., and Morales A. Membrane properties of primary sensory neurones of the cat after peripheral reinnervation. J. Physiol. (Lond.) 405: 219-232, 1988[Abstract/Free Full Text].

4.   Biscoe, T. J., and Pallot D. J. The carotid body chemoreceptor: an investigation in the mouse. Q. J. Exp. Physiol. 67: 557-576, 1982[Abstract/Free Full Text].

5.   Donnelly, D. Generation of interspike intervals of rat carotid body chemoreceptors. In: Frontiers in Arterial Chemoreception, edited by Zapata P., Eyzaguirre C., and Torrance R. W.. New York: Plenum, 1996, p. 169-174.

6.   Donnelly, D. F. Electrochemical detection of catecholamine release from rat carotid body in vitro. J. Appl. Physiol. 74: 2330-2337, 1993[Abstract/Free Full Text].

7.   Donnelly, D. F., and Doyle T. P. Developmental changes in hypoxia-induced catecholamine release from rat carotid body, in vitro. J. Physiol. (Lond.) 475: 267-275, 1994[Abstract/Free Full Text].

8.   Donnelly, D. F., Panisello J. M., and Boggs D. Effect of sodium perturbations on rat chemoreceptor spike generation: implications for a Poisson model. J. Physiol. (Lond.) 511: 301-311, 1998[Abstract/Free Full Text].

9.   Donnelly, D. F., Smith E. J., and Dutton R. E. Neural response of carotid chemoreceptors following dopamine blockade. J. Appl. Physiol. 50: 172-177, 1981[Abstract/Free Full Text].

10.   Drago, J., Padungchaichot P., Accili D., and Fuchs S. Dopamine receptors and dopamine transporter in brain function and addictive behaviors: insights from targeted mouse mutants. Dev. Neurosci. 20: 188-203, 1998[ISI][Medline].

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12.   Fidone, S., Gonzalez C., and Yoshizaki K. Effects of low oxygen on the release of dopamine from the rabbit carotid body in vitro. J. Physiol. (Lond.) 333: 93-110, 1982[Abstract/Free Full Text].

13.   Finley, J. C. W., Polak J., and Katz D. M. Transmitter diversity in carotid body afferent neurons: dopaminergic and peptidergic phenotypes. Neuroscience 51: 973-987, 1992[ISI][Medline].

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15.   Gehrich, J. L., and Moore G. P. Statistical analysis of cyclic variations in carotid body chemoreceptor activity. J. Appl. Physiol. 35: 642-648, 1973[Free Full Text].

16.   Gonzalez, C., Almaraz L., Obeso A., and Rigual R. Oxygen and acid chemoreception in the carotid body chemoreceptors. Trends Neurosci. 15: 146-153, 1992[ISI][Medline].

17.   Kholwadwala, D., and Donnelly D. F. Maturation of carotid chemoreceptor sensitivity to hypoxia: in vitro studies in the newborn rat. J. Physiol. (Lond.) 453: 461-473, 1992[Abstract/Free Full Text].

18.   Kline, D. D., Yang T., Huang P. L., and Prabhakar N. R. Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase. J. Physiol. (Lond.) 511: 273-287, 1998[Abstract/Free Full Text].

19.   Lahiri, S., Nishino T., Mokashi A., and Mulligan E. Interaction of dopamine and haloperidol with O2 and CO2 chemoreception in carotid body. J. Appl. Physiol. 49: 45-51, 1980[Abstract/Free Full Text].

20.   Mulligan, E., Alsberge M., and Bhide S. Carotid chemoreceptor recording in the newborn piglet. In: Arterial Chemoreception, edited by Eyzaguirre C., Fidone S. J., Fitzgerald R. S., Lahiri S., and McDonald D. M.. New York: Springer-Verlag, 1990, p. 285-289.

21.   Niu, W. Z., Engwall M. J. A., and Bisgard G. E. Two discharge patterns of carotid body chemoreceptors in the goat. J. Appl. Physiol. 69: 734-739, 1990[Abstract/Free Full Text].

22.   Nolan, W. F., Donnelly D. F., Smith E. J., and Dutton R. E. Nonrandom chemoreceptor activity during superfusion in vitro. Brain Res. 292: 194-197, 1984[Medline].

23.   Nye, P. C. G., and Powell F. L. Steady state discharge and bursting of arterial chemoreceptors in the duck. Respir. Physiol. 56: 369-384, 1984[Medline].

24.   Pepper, D. R., Landauer R. C., and Kumar P. Postnatal development of CO2-O2 interaction in the rat carotid body in vitro. J. Physiol. (Lond.) 485: 531-541, 1995[ISI][Medline].

25.   Vidruk, E. H., and Dempsey J. A. Carotid body chemoreceptor activity as recorded from the petrosal ganglion in cats. Brain Res. 181: 455-459, 1980[Medline].

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J APPL PHYSIOL 88(4):1489-1495
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J Appl Physiol, October 1, 2004; 97(4): 1401 - 1407.
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