Journal of Applied Physiology Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 98: 614-619, 2005; doi:10.1152/japplphysiol.00714.2004
8750-7587/05 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by He, L.
Right arrow Articles by Fidone, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by He, L.
Right arrow Articles by Fidone, S.

Effect of chronic hypoxia on cholinergic chemotransmission in rat carotid body

L. He, B. Dinger, and S. Fidone

Department of Physiology, University of Utah, Salt Lake City, Utah

Submitted 9 July 2004 ; accepted in final form 17 October 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Current views suggest that oxygen sensing in the carotid body occurs in chemosensory type I cells, which excite synaptically apposed chemoafferent nerve terminals in the carotid sinus nerve (CSN). Prolonged exposure in a low-oxygen environment [i.e., chronic hypoxia (CH)] elicits an elevated stimulus-evoked discharge in chemoreceptor CSN fibers (i.e., increased chemosensitivity). In the present study, we evaluated cholinergic chemotransmission in the rat carotid body in an effort to test the hypothesis that CH enhances ACh-mediated synaptic activity between type I cells and chemoafferent nerve terminals. Animals were exposed in a hypobaric chamber (barometric pressure = 380 Torr) for 9–22 days before evaluation of chemoreceptor activity using an in vitro carotid body/CSN preparation. Nerve activity evoked by ACh was significantly larger (P < 0.01) after CH, suggesting increased expression of cholinergic receptors. Approximately 80% of the CSN impulse activity elicited by ACh (100- or 1,000-µg bolus) in both normal and CH preparations was blocked by the specific nicotinic receptor antagonist mecamylamine (100 µM). CSN activity elicited by acute hypoxia or hypercapnia in normal preparations was likewise blocked (≥80%) in the presence of 100 µM mecamylamine, but after CH the enhanced CSN activity elicited by acute hypoxia or hypercapnia was not reduced in the presence of 100 or 500 µM mecamylamine. A muscarinic receptor antagonist, atropine (10 µM), and a specific nicotinic receptor {alpha}7 subunit antagonist, methyllycaconatine (50 nM), blocked ~50% of the hypoxia-evoked activity in normal preparations but were ineffective after CH. Prolonged exposure to hypoxia appears to dramatically alter chemotransmission in the carotid body, and may induce alternative neurotransmitter mechanisms and/or electrical coupling between type I cells and chemoafferent nerve terminals.

carotid sinus nerve; low-oxygen environment; acetylcholine; hypercapnia

CHRONIC EXPOSURE IN A LOW-OXYGEN (O2) environment [i.e., chronic hypoxia (CH)] initiates a multitude of physiological adjustments that tend to mitigate the adverse effects of hypoxia. Among the most important of these adaptive changes is increased ventilation, evident as elevated tidal volume and/or frequency of breathing. CH, lasting for hours or days, initiates a time-dependent increase in breathing known as ventilatory acclimatization to hypoxia (VAH). In rats, VAH progresses over a 4- to 5-day period, and enhanced breathing persists for at least 14 days (25). Attempts to identify the structures that mediate VAH have focused principally on the carotid chemoreflex pathway, which consists of multiple components, including 1) chemoreceptor type I (glomus) cells in the carotid body; 2) chemoafferent neurons of the petrosal ganglion (PG), which innervate the type I cells via the carotid sinus nerve (CSN); 3) a complex circuit of brain stem neurons in proximity to the caudal nucleus tractus solitarius; and 4) respiratory phrenic motoneurons.

Chemoreceptor type I cells have been identified as chemotransductive elements in the carotid body. Pharmacological assessments and direct measurements of putative neurotransmitters suggest that, in response to appropriate natural stimuli (e.g., low O2), these cells release a variety of neuroactive agents, including dopamine, acetylcholine (ACh), ATP, and neuropeptides (for reviews, see Refs. 15, 16). In view of the fact that CSN discharge is increased on exposure to CH (2, 3, 31), numerous studies have focused on elucidating adaptive changes in type I cells. Indeed, these efforts demonstrated adjustments in the functional properties of type I cells, including altered membrane currents, as well as changes in the metabolism and actions of endogenous neurotransmitters and neuropeptides (19–21, 29).

In the central nervous system, other investigations have focused on the brain stem neurons, which receive the projections from CSN chemoafferents. In a series of studies (reviewed in Ref. 28), Pequignot and colleagues have shown that CH increases turnover of norepinephrine and upregulates tyrosine hydroxylase, the rate-limiting enzyme for catecholamine production, in a select subgroup of neurons in the caudal nucleus tractus solitarius. These neurochemical adjustments did not occur after acute hypoxia, suggesting that they are involved in the increased ventilatory response. Consistent with central readjustments, Powell et al. (26a) showed that CH facilitates the translation of chemoafferent input into ventilatory efferent output. Moreover, these findings were correlated with a decrease in the expression of the D2 subtype of dopamine receptors in the nucleus tractus solitarius, which have been shown to stimulate respiration (6).

Although type I cells and central neurons have been identified as potential contributors to VAH, the phenomenon nonetheless remains only partially understood. In fact, an important element in the chemoreflex pathway, namely, the chemoafferent PG neurons, has been largely ignored as possible adaptive components. Studies in other pathways have shown that certain primary sensory neurons undergo significant physiological adjustments in response to chronic stimulation. For example, chronic pain involving inflammation induces substantial changes in neuropeptide synthesis in neuron cell bodies and increases neurotransmitter release at peripheral and central projections (8, 17). Moreover, peripheral nerve injury or chronic inflammation induces altered expression of neurotransmitter receptors by dorsal root ganglion neurons (24, 30).

Recent immunocytochemical studies have demonstrated the expression of nicotinic cholinergic receptors in PG neurons and afferent fiber terminals in the carotid body (27). Furthermore, cocultures of type I cells and PG neurons display synaptic properties consistent with cholinergic chemotransmission (34, 35). The possibility that CH induces significant adaptive change in the expression of nicotinic cholinergic receptors on PG neurons innervating rat carotid body chemoreceptors has come from recent studies in our laboratory that showed increased expression of {alpha}3- and {alpha}7-nicotinic receptor subunits after 9–14 days of hypobaric (380 Torr) hypoxia (13). These findings were correlated with increased antidromic nerve impulse traffic elicited in the CSN by the application of ACh to the PG after CH. In the present study, we have examined the hypothesis that CH-induced change in the expression of cholinergic receptors is correlated with enhanced cholinergic chemotransmission in the carotid body. Surprisingly, our findings suggest that CH results in a diminished contribution of cholinergic transmission at the chemosensory synapse between O2-sensitive type I cells and CSN afferent terminals.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals and exposure to hypobaric hypoxia.   Animal protocols were approved by the University of Utah Institutional Animal Care and Use Committee. Twenty-three adult male albino Sprague-Dawley rats (180–200 g) were housed in standard rodent cages with 24-h access to pellet food and water. Cages containing two to four rats were placed in a hypobaric chamber; pressure was decrementally lowered from ambient (~640 Torr at Salt Lake City, 1,400 m) over a 24- to 36-h period to 380 Torr (equivalent to 5,500 m). Because previous studies in our laboratory demonstrated that increased CSN hypoxic chemosensitivity plateaus after 9 days (10), animals were maintained in the hypobaric environment for 9–22 days. The chamber was opened briefly at 2-day intervals to replenish food and water. Age-matched control male rats were similarly housed at ambient pressure.

Electrophysiological recording of CSN activity.   Rats were anesthetized with ketamine (10 mg/100 g im) plus xylazine (0.9 mg/100 g im), and the carotid artery bifurcations containing the carotid bodies were located and removed. The excised tissue was placed in a Lucite chamber containing 100% O2-equilibrated modified Tyrode solution at 0–4°C (in mM: 112 NaCl, 4.7 KCl, 2.2 CaCl2, 1.1 MgCl2, 42 sodium glutamate, 5 HEPES buffer, 5.6 glucose, pH = 7.4). Each carotid body along with its attached nerve was carefully dissected from the artery, cleaned of surrounding connective tissue, and placed in a conventional flow chamber, where the carotid body was continuously superfused (up to 4 h) with modified Tyrode solution maintained at 37°C and equilibrated with a selected gas mixture. For studies involving hypercapnic stimulation, preparations were maintained in bicarbonate-buffered solution consisting of (in mM) 116 NaCl, 24 NaHCO3, 5 KCl, 2 CaCl2, 1.1 MgCl2, 5.5 glucose, and 10 HEPES buffer. This solution was continuously bubbled with 5% CO2-95% O2 (pH 7.4 at 37°C). For isohydric hypercapnic stimulation, the NaHCO3 concentration was increased to 96 mM (reduction in NaCl to 44 mM), and the solution was bubbled with 20% CO2-80% O2 resulting in a pH of 7.4 at 37°C.

The CSN was drawn up into the tip (~100-µm inner diameter) of a glass suction electrode for monopolar recording of chemoreceptor activity. Sufficient suction was applied to seal the electrode tip against connective tissue encircling the junction of the carotid body and CSN. The bath was grounded with a Ag-AgCl2 wire, and neural activity was led to an alternating current-coupled preamplifier, filtered, and transferred to a window discriminator and a frequency-to-voltage converter. Signals were processed by an analog-to-digital converter for display of frequency histograms on a personal computer monitor. Data were expressed as impulses per second and analyzed using ANOVA with Bonferroni multiple comparison posttests or paired t-tests. Bolus injections of 100 or 1,000 µg of ACh contained in 100 µl were delivered immediately upstream of the carotid body. Bath PO2 was measured with a Diamond General model 760 needle electrode, connected to a Harvard model 102 O2 electrode amplifier.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
CH-induced increased sensitivity to ACh.   Figure 1 shows CSN activity elicited by ACh application to the carotid body in normoxic vs. CH preparations. Basal (resting) activity in these superfused (nonvascular) preparations was established in solutions equilibrated with 100% O2, resulting in a bath PO2 of ~450 Torr and a mean basal nerve discharge rate of 11 ± 1.3 impulses/s (mean ± SE). In Fig. 1A, the application of a 1,000-µg bolus elicited a sharp increase in nerve activity, which gradually returned to the basal discharge rate. After 10–21 days of CH (Fig. 1B), application of 100 g or 1,000 µg of ACh also elicited an immediate response; however, in these preparations, the peak and total evoked activity were substantially larger than normal. Summary data for the evoked activity in these experiments are shown in Fig. 1C, which demonstrates that exposure to a 100- and 1,000-µg bolus of ACh elicited significantly larger total CSN responses in preparations from rats that had been exposed to CH.



View larger version (27K):
[in this window]
[in a new window]
  		Fig. 1. Acetylcholine (ACh)-evoked carotid sinus nerve (CSN) activity is enhanced after chronic hypoxia (CH). A: CSN activity evoked by a 1,000-µg bolus of ACh in a normal carotid body superfused in vitro. B: CSN activity evoked by 1,000-µg bolus of ACh applied to a superfused carotid body excised from a rat after 14 days of CH (380 Torr). C: summary data of ACh-evoked (100- or 1,000-µg bolus) CSN activity in normal and CH preparations (9–22 days at 380 Torr). Data are expressed as total evoked impulses minus basal nerve discharge rate [impulses (imp)/s]. Values in parentheses denote n value. Significant difference vs. normal values: **P < 0.01; ***P < 0.001.

 
Effect of mecamylamine on ACh-evoked CSN activity.   The role of nicotinic cholinergic receptors in these responses was further investigated in experiments utilizing the specific nicotinic receptor antagonist mecamylamine. In these experiments, the application of mecamylamine did not alter basal nerve activity in either normal or CH preparations. However, the antagonist severely attenuated CSN activity evoked by ACh. Figure 2, A and B, shows that 100 µM mecamylamine blocked ~80% of CSN activity evoked by a 100-µg bolus of ACh in normal and CH preparations, respectively, confirming the involvement of nicotinic cholinergic receptors.



View larger version (49K):
[in this window]
[in a new window]
  		Fig. 2. Effect of nicotinic receptor antagonist mecamylamine on ACh-evoked CSN activity in normal and CH (9–22 days at 380 Torr) carotid bodies superfused in vitro. Top: 3 superimposed records of integrated neural activity evoked by ACh in the presence or absence (control and recovery) of 100 µM mecamylamine in normal (left) and CH (right) preparations. Bottom: summary data for 7 normal and 5 CH preparations are normalized to control response. C, control; M, mecamylamine; R, recovery. Approximately 80% of ACh-evoked activity is blocked by the nicotinic antagonist. Significant difference compared with activity evoked by ACh alone: **P < 0.01 and ***P < 0.001.

 
Effect of mecamylamine on hypoxia-evoked chemoreceptor activity.   The possibility that CH elicits enhanced cholinergic chemotransmission between type I cells and afferent fiber terminals was tested by examining the effects of mecamylamine on CSN activity evoked by acute hypoxia in vitro. Figure 3, top, shows CSN activity evoked by a standard hypoxic stimulus (150 s at a PO2 of 120 Torr) in the presence or absence of the nicotinic antagonist. The mean basal (resting) discharge rate established at a PO2 of ~450 Torr in normal preparations was 9.35 ± 0.73 impulses/s. Hypoxia applied to a normal preparation (Fig. 3A, top) evoked a rapid increase in nerve discharge, which returned to the basal level of activity within a few seconds of reintroduction of oxygenated media. In the presence of 100 µM mecamylamine (superimposed trace), the basal discharge rate was not significantly altered, but the effect of hypoxia was dramatically reduced, consistent with nicotinic cholinergic chemotransmission. After a 20-min washin of drug-free oxygenated media, the hypoxic response is fully recovered. Summary data (Fig. 3A, bottom) indicate that, on average, mecamylamine blocks ~80% of the hypoxia-evoked nerve discharge in normal preparations. Figure 3, B and C, shows that, after 9–22 days of CH, mecamylamine applied at concentrations of 100 µM (Fig. 3B) and 500 µM (Fig. 3C) is completely ineffective against either basal or hypoxia-evoked CSN activity, resulting in indistinguishable superimposed physiological records. In these CH preparations, the basal and hypoxia-evoked activity was significantly larger than normal (note different scales for Fig. 3A vs. Fig. 3, B and C), as has been documented in our laboratory's previous studies (10).



View larger version (38K):
[in this window]
[in a new window]
  		Fig. 3. Effect of mecamylamine on hypoxia-evoked CSN activity in normal and CH (9–22 days at 380 Torr) carotid bodies superfused in vitro. Top, left: 3 superimposed traces for a normal preparation show that 100 µM mecamylamine is a potent blocker of CSN activity evoked by a standard hypoxic stimulus (see RESULTS). Bottom, left: summary data (n = 3) demonstrate that the nicotinic receptor antagonist blocks ~80% of the hypoxia-evoked nerve discharge. Middle and right: mecamylamine at 100 µM (middle; n = 6) and 500 µM (right; n = 3) is without effect on hypoxia-evoked CSN activity after CH. ***Significant difference vs. control response (P < 0.001).

 
Effect of other cholinergic receptor antagonists on hypoxia-evoked nerve activity.   Similar experiments compared the effects of an alternate nicotinic receptor antagonist, methyllycaconitine (50 nM), which binds to the {alpha}7-subunit of the receptor (12), and a general muscarinic antagonist, atropine (10 µM). Summary data presented in Fig. 4 show that these agents inhibit ~50% of hypoxia-evoked activity in normal preparations, but, like mecamylamine, they are completely ineffective after CH (11–15 days at 380 Torr). As with mecamylamine, methyllycaconitine and atropine did not significantly affect the resting nerve activity in normal or CH preparations. It is noteworthy that, at the concentration used here, atropine may interact with both muscarinic and nicotinic receptors (26).



View larger version (57K):
[in this window]
[in a new window]
  		Fig. 4. Summary data showing effect of 10 µM atropine (muscarinic receptor antagonist) and 50 nM methyllycaconitine (MLA; {alpha}7-subunit nicotinic receptor antagonist) on CSN activity evoked by a standard hypoxic stimulus (see RESULTS). After 11–15 days of CH (380 Torr), atropine and MLA are ineffective blockers of hypoxia-evoked activity. ***Significant difference vs. normal (P < 0.001).

 
Effect of mecamylamine on chemoreceptor activity evoked by hypercapnia.   Figure 5 shows the effect of 14 days of CH on CSN responses evoked by isohydric hypercapnia (20% CO2, pH 7.4). In four normal preparations, this strong hypercapnic stimulus elicited an increase in nerve activity that was larger than responses elicited by moderate hypoxia. The hypercapnia-evoked CSN activity was nearly completely blocked by 100 µM mecamylamine (see Fig. 5, superimposed traces in top; summary data, bottom). In contrast, after CH (n = 4), hypercapnia elicited a rapid and markedly larger increase in CSN activity that was completely resistant to mecamylamine, resulting in indistinguishable, superimposed records of integrated nerve activity in the presence vs. absence of the drug. Thus, after CH, responses elicited by either hypoxia or hypercapnia are resistant to the nicotinic receptor antagonist.



View larger version (36K):
[in this window]
[in a new window]
  		Fig. 5. Effect of mecamylamine on hypercapnia-evoked CSN activity in normal and CH (14 days at 380 Torr) carotid bodies superfused in vitro. Top, left: 3 superimposed traces for a normal preparation show that 100 µM mecamylamine is a potent blocker of CSN activity evoked by a standard isohydric hypercapnic stimulus (see RESULTS). Bottom, left: summary data (n = 4) demonstrate that the nicotinic receptor antagonist blocks >95% of the hypercapnia-evoked nerve discharge. Right: mecamylamine at 100 µM (n = 4) is without effect on hypercapnia-evoked CSN activity after CH. ***Significant difference vs. control response (P < 0.001).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our previous experiments demonstrated increased ACh-evoked antidromic activity in the CSN after CH, indicating that PG neuron cell bodies express higher levels of cell surface cholinergic receptors in response to prolonged hypoxic stress (13). The present study extends these findings by showing increased nicotinic receptor-mediated responses in afferent axon fiber terminals that innervate glomus (type I) cells in the carotid body. Thus ACh applied to the carotid body after CH elicits a significantly larger response in the CSN, ~80% of which is blocked by the nicotinic receptor antagonist mecamylamine.

Multiple studies document increased chemosensitivity to hypoxia after CH, apparent both as elevated activity in the CSN and an enhanced hypoxic ventilatory response (1, 2, 4, 31). The present findings indicate that PG neurons express higher levels of nicotinic receptors after CH, which is consistent with the hypothesis that nicotinic receptors contribute to enhanced chemosensitivity. However, the failure of nicotinic and muscarinic blockers to depress the CSN discharge evoked by acute hypoxia after prolonged exposure to hypobaric hypoxia indicates that cholinergic chemotransmision is not involved in this adaptive phenomenon. In fact, our data indicate that, despite a substantial augmentation of the nicotinic receptor population, cholinergic synaptic activity is severely depressed. The present findings do not reveal whether this dramatic change in cholinergic activity may involve the failure of ACh synthesis and/or release. It is noteworthy that numerous pharmacological and immunocytochemical studies have supported cholinergic chemotrasmission at the chemoreceptor synapse (see Refs. 15, 16, 27, 34, 35). Moreover, a recent study in rabbit carotid body demonstrated that hypercapnia evokes the release of ACh and that muscarinic receptors modulate this response (23). However, other important data call into question the expression of classical cholinergic properties in rat type I cells (18).

It is well established that CH induces enlargement of the carotid body, such that organ size is increased approximately threefold after 14 days of hypoxia (10). In our in vitro superfused preparations, increased size could conceivably create more severe internal hypoxia, which may render mecamylamine ineffective during CH. However, multiple observations suggest that greater organ mass does not explain mecamylamine resistance. First, steeper O2 diffusion gradients should result in elevated mecaylamine-sensitive basal nerve activity. Although the basal nerve activity was increased after CH in accord with our previous observations (10), it was completely insensitive to cholinergic antagonists. Second, switching the superfusate does not instantaneously lower PO2 in the bath; rather, PO2 is incrementally lowered through intermediate levels of hypoxia (see Figs. 5 and 6 in Ref. 13). Yet the presence of mecamylamine did not alter the onset of CSN activity during these transitions, resulting in indistinguishable physiological records in the presence of antagonists (Fig. 3). Finally, after CH, mecamylaine was also ineffective against CSN activity elicited by hypercapnia, a stimulus that has been demonstrated to release ACh from rabbit type I cells (23). Collectively, these data strongly suggest that cholinergic activity is severely downregulated after CH.

The loss of cholinergic synaptic activity suggests that an alternative mechanism may mediate chemotransmission after CH. Recent studies by Nurse and colleagues have demonstrated coparticipation of cholinergic and purinergic mechanisms in synapses formed between co-cultured type I cells and PG neurons (7, 34, 35). These studies have shown that PG neurons and their afferent terminals express P2X2 purinergic receptors, as well as nicotinic cholinergic receptors, and that a cocktail of specific nicotinic/purinergic antagonists completely blocks hypoxic chemotransnmission. The current data are consistent with an expanded role for purinergic and/or other transmitter mechanisms at the chemoreceptor synapse after CH. However, previous studies of serotonin, dopamine, and various neuropeptides have not yielded compelling evidence of an essential role for these agents in excitatory synaptic transmission and/or increased chemosensitivity (5, 32). Noteworthy are recent studies in our laboratory indicating that endothelin (ET), a vasoactive peptide contained in type I cells, is a critical participant in the elevated chemoreceptor discharge associated with CH (10). However, expression of ET receptors by PG neurons and chemoafferent terminals was not evident, and the actions of ET in the CH carotid body appears to be mediated via an autocrine/paracrine (nonsynaptic) mechanism involving specific ET A receptors located on type I cells.

An additional putative synaptic mechanism yet to be fully explored is electrical coupling between type I cells and chemoafferent terminals. Although chemical mechanisms may dominate synaptic activity in the normal carotid body, a recent study by Jiang and Eyzaguirre (22) suggests that electrical junctions also exist between type I cells and nerve terminals. Thus it is possible that our recent demonstration of increased expression of connexin proteins in type I cells and PG neurons after CH (11) correlates with newly formed gap junctions that could mediate afferent terminal depolarization via intercellular ionic currents. Such enhanced electrical coupling could provide an adaptive advantage by reducing the need for energetically expensive neurotransmitter synthesis and release during periods of prolonged hypoxic stress. Finally, our data are consistent with the possibility that CH induces hypoxic sensitivity in chemoafferent nerve terminals. In this regard, Campanucci et al. (9) have recently reported the existence of a subpopulation of PG neurons in normal rats that express O2-sensitive K+ channels.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institute of Neurological Disorders and Stroke Grants NS-12636 and NS-07938.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. Dinger, Dept. of Physiology, Univ. of Utah, 410 Chipeta Way, Research Park, Salt Lake City, UT 84108-1297 (E-mail: Bruce.Dinger{at}m.cc.utah.edu)

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. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Aaron EA and Powell FL. Effect of chronic hypoxia on hypoxic ventilatory response in awake rats. J Appl Physiol 74: 1635–1640, 1993.[Abstract/Free Full Text]
  2. Barnard P, Andronikou S, Pokorski M, Smatresk N, Mokashi A, and Lahiri S. Time-dependent effect of hypoxia on carotid body chemosensory function. J Appl Physiol 63: 685–691, 1987.[Abstract/Free Full Text]
  3. Bisgard GE. The role of arterial chemoreceptors in ventilatory acclimatization to hypoxia. In: Advances in Experimental Medicine and Biology. Arterial Chemoreceptors: Cell to System, edited by O'Regan RG, Nolan P, McQueen DS, and Paterson DJ. New York, Plenum, 1994, vol. 360, p. 109–122.
  4. Bisgard GE. Increase in carotid body sensitivity during sustained hypoxia. Biol Signals 4: 292–297, 1995.[ISI][Medline]
  5. Bisgard GE. Carotid body mechanisms in acclimatization to hypoxia. Respir Physiol 121: 237–246, 2000.[CrossRef][ISI][Medline]
  6. Bolme P, Fuxe K, Hokfelt T, and Goldstein M. Studies on the role of dopamine in cardiovascular and respiratory control: central versus peripheral mechanisms. Adv Biochem Psychopharmacol 16: 281–290, 1997.
  7. Buttigieg J and Nurse C. Detection of hypoxia-evoked ATP release from chemoreceptor cells of the rat carotid body. Biochem Biophys Res Commun 322: 82–87, 2004.[CrossRef][ISI][Medline]
  8. Calza L, Pozza M, Zanni M, Manzini CU, Manzini E, and Hokfelt T. Peptide plasticity in primary sensory neurons and spinal cord during adjuvant-induced arthritis in the rat: an immunocytochemical and in situ hybridization study. Neuroscience 82: 575–589, 1998.[CrossRef][ISI][Medline]
  9. Campanucci VA, Fearon IM, and Nurse CA. A novel O2-sensing mechanism in rat glossopharyngeal neurones mediated by a halothane-inhibitable background K+ conductance. J Physiol 548: 731–743, 2003.[Abstract/Free Full Text]
  10. Chen J, He L, Dinger B, Stensaas L, and Fidone S. Role of endothelin and endothelin A-type receptor in physiological adaptation of the carotid body during chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 282: L1314–L1323, 2002.[Abstract/Free Full Text]
  11. Chen J, He L, Dinger B, Stensaas L, and Fidone S. Chronic hypoxia upregulates connexin43 expression in rat carotid body and petrosal ganglion. J Appl Physiol 92: 1480–1486, 2002.[Abstract/Free Full Text]
  12. Davies AR, Hardick DJ, Blagbrough IS, Potter BV, Wolstenholme AJ, and Wonnacott S. Characterisation of the binding of [3H]methyllycaconitine: a new radioligand for labeling alpha 7-type neuronal nicotinic acetylcholine receptors. Neuropharmacology 38: 679–690, 1999.[CrossRef][ISI][Medline]
  13. Dinger B, He L, Chen J, Stensaas L, and Fidone S. Mechanisms of morphological and functional plasticity in the chronically hypoxic carotid body. In: Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by Lahiri S, Semenza G, and Prabhakar N. New York: Dekker, 2003, p. 439–465.
  14. Fidone SJ and Gonzalez C. Initiation and control of chemoreceptor activity in the carotid body. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 1, chapt. 9, p. 247–312.
  15. Fidone SJ, Gonzalez C, Almaraz L, and Dinger B. Cellular mechanisms of peripheral chemoreceptor function. In: The Lung: Scientific Foundations, edited by Crystal RG and West JB. Philadelphia, PA: Lippincott-Raven, 1997, p. 1725–1746.
  16. Galeazza MT, Garry MG, Yost HJ, Strait KA, Hargreaves KM, and Seybold VS. Plasticity in the synthesis and storage of substance P and calcitonin gene-related peptide in primary afferent neurons during peripheral inflammation. Neuroscience 66: 443–458, 1995.[CrossRef][ISI][Medline]
  17. Gauda EB. Gene expression in peripheral arterial chemoreceptors. Microsc Res Tech 59: 153–167, 2002.[CrossRef][ISI][Medline]
  18. Gonzalez-Guerrero PR, Rigual R, and Gonzalez C. Effects of chronic hypoxia on opioid peptide and catecholamine levels and on the release of dopamine in the rabbit carotid body. J Neurochem 60: 1769–1776, 1993.[CrossRef][ISI][Medline]
  19. Hanbauer I, Karoum F, Hellstrom S, and Lahiri S. Effects of hypoxia lasting up to one month on the catecholamine content in rat carotid body. Neuroscience 6: 81–86, 1981.[CrossRef][ISI][Medline]
  20. Jackson A and Nurse C. Dopaminergic properties of cultured rat carotid body chemoreceptors grown in normoxic and hypoxic environments. J Neurochem 69: 645–654, 1997.[ISI][Medline]
  21. Jiang RJ and Eyzaguirre C. Dye and electric coupling between carotid nerve terminals and glomus cells. In: Chemoreception: From Cellular Signaling to Functional Plasticity, edited by Pequignot J, Gonzalez C, Nurse C, Prabhakar NR, and Dalmaz Y. New York: Plenum, 2003, p. 247–253.
  22. Kim DK, Prabhakar N, and Kumar GK. Acetylcholine release from the carotid body by hypoxia: evidence for the involvement of autoinhibitory receptors. J Appl Physiol 96: 376–383, 2004.[Abstract/Free Full Text]
  23. Okamoto K, Imbe H, Morikawa Y, Itoh M, Sekimoto M, Nemoto K, and Senba E. 5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rat. Pain 99: 133–143, 2000.
  24. Olson EB Jr and Dempsey JA. Rat as a model for humanlike ventilatory adaptation to chronic hypoxia. J Appl Physiol 44: 763–769, 1978.[Abstract/Free Full Text]
  25. Parker JC, Sarkar D, Quick MW, and Lester RAJ. Interactions of atropine with heterologously expressed and native {alpha}3 subunit-containing nicotinic acetylcholine receptors. Br J Pharmacol 138: 801–810, 2003.[CrossRef][ISI]
  26. Powell FL, Huey KA, and Dwinell MR. Central nervous system mechanisms of ventilatory acclimitization to hypoxia. Respir Physiol 121: 223–236, 2000.[CrossRef][ISI][Medline]
  27. Shirahata M, Ishizawa Y, Rudisill M, Schofield B, and Fitzgerald RS. Presence of nicotinic acetylcholine receptors in cat carotid body afferent system. Brain Res 814: 213–217, 1998.[CrossRef][ISI][Medline]
  28. Soulier V, Gestreau C, Borghini N, Dalmaz Y, Cottet-Emard JM, and Pequignot JM. Peripheral chemosensitivity and central integration: neuroplasticity of catecholaminergic cells under hypoxia. Comp Biochem Physiol A 118: 1–7, 1997.[Medline]
  29. Stea A, Jackson A, and Nurse CA. Hypoxia and N6,O2-dibutyryladenosine 3',5'-cyclic monophosphate, but not nerve growth factor, induce Na+ channels and hypertrophy in chromaffin-like arterial chemoreceptors. Proc Natl Acad Sci USA 82: 9469–9473, 1992.
  30. Tsuzuki K, Kondo E, Fukuoka T, Yi D, Tsujino H, Sakagami M, and Nogucl K. Differential regulation of P2X3 mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91: 351–360, 2001.[CrossRef][ISI][Medline]
  31. Vizek M, Pickett CK, and Weil JV. Increased carotid body hypoxic sensitivity during acclimitization to hypobaric hypoxia. J Appl Physiol 63: 2403–2410, 1987.[Abstract/Free Full Text]
  32. Wang ZY and Bisgard GE. Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59: 168–177, 2002.[CrossRef][ISI][Medline]
  33. Wang ZZ, Stensaas LJ, Dinger B, and Fidone SJ. Immunocytochemical localization of choline acetyltransferase in the carotid body of the cat and rabbit. Brain Res 498: 131–134, 1989.[CrossRef][ISI][Medline]
  34. Zhang M and Nurse C. CO2/pH chemosensory signaling in co-cultures of rat carotid body receptors and petrosal neurons: role of ATP and ACh. J Neurophysiol. First published March 31, 2004; doi:10.1152/jn.01099.2003.
  35. Zhang M, Zhong H, Vollmer C, and Nurse CA. Co-release of ATP and ACh mediates hypoxic signaling at rat carotid body chemoreceptors. J Physiol 525: 143–158, 2000.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
D. F. Donnelly
Spontaneous action potential generation due to persistent sodium channel currents in simulated carotid body afferent fibers
J Appl Physiol, May 1, 2008; 104(5): 1394 - 1401.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
S. V. Conde, A. Obeso, and C. Gonzalez
Low glucose effects on rat carotid body chemoreceptor cells' secretory responses and action potential frequency in the carotid sinus nerve
J. Physiol., December 15, 2007; 585(3): 721 - 730.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. He, J. Chen, X. Liu, B. Dinger, and S. Fidone
Enhanced nitric oxide-mediated chemoreceptor inhibition and altered cyclic GMP signaling in rat carotid body following chronic hypoxia
Am J Physiol Lung Cell Mol Physiol, December 1, 2007; 293(6): L1463 - L1468.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
A. Balbir, H. Lee, M. Okumura, S. Biswal, R. S. Fitzgerald, and M. Shirahata
A search for genes that may confer divergent morphology and function in the carotid body between two strains of mice
Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L704 - L715.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. Zhang, J. Buttigieg, and C. A. Nurse
Neurotransmitter mechanisms mediating low-glucose signalling in cocultures and fresh tissue slices of rat carotid body
J. Physiol., February 1, 2007; 578(3): 735 - 750.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
L. He, J. Chen, B. Dinger, L. Stensaas, and S. Fidone
Effect of chronic hypoxia on purinergic synaptic transmission in rat carotid body
J Appl Physiol, January 1, 2006; 100(1): 157 - 162.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by He, L.
Right arrow Articles by Fidone, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by He, L.
Right arrow Articles by Fidone, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.