AJP - Regu Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 287: R369-R374, 2004. First published April 15, 2004; doi:10.1152/ajpregu.00128.2004
0363-6119/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/2/R369    most recent
00128.2004v1
Right arrow Alert me when this article is cited
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 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 Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reeves, S. R.
Right arrow Articles by Gozal, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reeves, S. R.
Right arrow Articles by Gozal, D.

ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

Platelet-activating factor receptor modulates respiratory adaptation to long-term intermittent hypoxia in mice

Stephen R. Reeves and David Gozal

Departments of Pediatrics and Pharmacology and Toxicology, Kosair Children's Hospital Research Institute, University of Louisville School of Medicine, Louisville, Kentucky 40202

Submitted 24 February 2004 ; accepted in final form 14 April 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
During hypoxia, release of platelet-activating factor (PAF) and activation of its cognate receptor (PAFR) regulate neural transmission and are required for full expression of peak hypoxic ventilatory response (pHVR) but not hypercapnic ventilatory response. However, it is unclear whether PAFR underlie components of long-term ventilatory adaptations to hypoxia. To examine this issue, adult male PAFR(+/+) and PAFR(–/–) mice were exposed to intermittent hypoxia (IH) consisting of 90 s 21% O2 and 90 s 10% O2 for 30 days, and normoxic and hypoxic ventilatory patterns were assessed using whole body plethysmography. Starting at day 14 of IH, normoxic ventilation in PAFR(–/–) was reduced significantly compared with PAFR(+/+) mice (P < 0.001), the latter exhibiting a prominent long-term ventilatory facilitation (LTVF). However, IH-exposed PAFR(–/–) mice had markedly enhanced pHVR and hypoxic ventilatory decline that became similar to those of IH-exposed PAFR(+/+) mice. Thus we postulate that PAFR expression and/or function underlies critical components of IH-induced LTVF but does not play a role in the potentiation of the hypoxic ventilatory response after IH exposures.

respiratory control; hypoxia; synaptic plasticity; central chemosensitivity; ventilatory adaptation; long-term facilitation

PLATELET-ACTIVATING FACTOR (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) is a biologically active phospholipid that is now well established in its multifaceted roles involving several biological activities and tissue locations, including the central nervous system (CNS; see Refs. 3 and 22). In the CNS, PAF is primarily synthesized through a de novo mechanism involving cytidine diphosphate choline-1-O-2-acetyl-sn-glycerolcholine phosphotransferase (CGCP), which mediates the transfer of phosphocholine to alkylacetyl-sn-glycerol (28). CGCP is abundant in the rodent brain and is responsive to both physiological and pathological stimulation such as tissue ischemia/hypoxia, high-frequency electrical stimuli, and neurotransmitters such as ACh and dopamine in a Ca2+-dependent manner (8, 9, 13, 28, 40, 47, 50). Thus PAF has emerged as an important mediator of both excitotoxic injury and of synaptic transmission and neural plasticity, such as long-term potentiation (LTP; see Refs. 8, 9, 13, 28, 40, 47, 50).

Expression of the PAF receptor (PAFR) in the CNS has been demonstrated in both neurons and microglia (35) and may also colocalize with N-methyl-D-aspartate glutamate receptors in hippocampal neurons (8). PAF application modulates neuronal differentiation, calcium fluxes, and LTP (4, 10, 23, 26, 27, 55), and the latter can be blocked by administration of the PAFR antagonist BN-52021, both in vivo and in vitro, thereby supporting a role for PAF as a retrograde messenger during neuronal activation (21, 23, 25, 32).

PAFR are constitutively expressed in the pontomedullary regions in relative abundance (6–8), and microinjection of a long-acting PAF analog in the dorsocaudal brain stem induces significant ventilatory enhancements (16). Conversely, local or systemic administration of BN-52021 was associated with substantial attenuation of the hypoxic ventilatory response (HVR), but not of the hypercapnic ventilatory response (16), and this effect was primarily mediated through changes in tidal volume (VT) without significant changes in the frequency responses (16, 49). We recently confirmed these findings using a transgenic mouse model deficient in the PAFR [PAFR(–/–); see Ref. 43]. In the same study, PAFR(–/–) animals displayed marked differences in their metabolic responses when exposed to an acute hypoxic environment (43). However, although PAFR activity is now clearly implicated in acute components of the HVR, it remains unclear whether PAFR play any role in long-term ventilatory adaptations to hypoxia.

To further examine this issue, we took advantage of the unique long-term ventilatory effects induced by exposures to intermittent hypoxia (IH; see Refs. 33, 38, 42, 44, 48, 54) and exposed wild-type adult male mice [PAFR(+/+)] and PAFR(–/–) mice to IH for a period of 30 days, during which ventilatory responses were assessed. We hypothesized that PAFR(–/–) mice would have maladaptive responses to long-term hypoxia exposures and therefore provide further insight in the role(s) of PAFR in the ventilatory adaptations to hypoxia.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The experimental protocols were approved by the Institutional Animal Use and Care Committee and are in close agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Animals. Breeding pairs of PAFR-deficient mice (hybrids between C57BL/6J and 129/Ola) and their wild-type littermates were developed by Dr. Takao Shimizu and provided by Dr. Nicholas Bazan (Louisiana State University, New Orleans, LA). Littermates were genotyped according to previously reported procedures (19). Briefly, Quick Tail DNA Prep for Genotyping (1 mm mouse tail) was obtained under halothane anesthesia, added to digestion buffer [5 mM EDTA, 200 mM NaCl, 100 mM Tris·HCl (pH 8.0; 0.2% SDS), 0.5 mg/ml proteinase K, and 12.5 mg/ml RNase A], and digested overnight in a hybridization oven at 55°C. The DNA was extracted with phenol-chloroform-isoamyl alcohol (25:24:1), washed two times in chloroform-isoamyl alcohol (26:4), and precipitated with 1:1 isopropanol. Pellets were resuspended in Tris-EDTA (pH 8) and heated for 2 h at 65°C. PCR was as follows: 0.5 ml DNA, 13 ml PCR buffer, 1.5 mM MgCl, 0.1 mM dNTPs, 200 ng primers (forward: 59-gcc tgc ttg ccg at atc atg gtg gaa aat-39, reverse: 39-gcg atg cgc tgc gaa tcg gga gcg gcg ata-59 for deficient allele and forward: 59-tat ggc tga cct gct ctt cct gat-39, reverse: 39-tat tgg gca cta ggt tgg tgg agt-59 for wild-type allele), 11.5 ml water, and 1 unit Taq DNA Polymerase in a total volume of 25 ml. PCR was carried out using a Perkin-Elmer GeneAmp PCR System 9600 cycler with the following conditions: 94°C for 0.25 min, 60°C for 0.25 min, and 72°C for 0.5 min for 30 cycles. The PCR product was then analyzed on a 1.8% agarose gel containing ethidium bromide.

IH exposures. Animals were placed in four identical commercially designed chambers (30 x 20 x 20 in.; Oxycycler model A44XO; Biospherix, Redfield, NY) that were operated under a 12:12-h light-dark cycle (6:00 AM-6:00 PM). Gas was circulated around each of the chambers, attached tubing, and other units at 60 l/min (i.e., 1 complete change/10 s). The O2 concentration was measured continuously by an O2 analyzer and was changed by a computerized system controlling the gas valve outlets such that the moment-to-moment desired O2 concentration of the chamber was programmed and adjusted automatically. Deviations from the desired concentration were met by addition of N2 or O2 through solenoid valves. Ambient CO2 in the chamber was monitored periodically and maintained at <0.01% by adjusting overall chamber basal ventilation. Humidity was measured and maintained at 40–50% by circulating the gas through a freezer and silica gel. Ambient temperature was kept at 22–24°C. The IH profile consisted of alternating room air and 10% O2 every 90 s for the 12 h of light period. Control animals were exposed to circulating normoxic gas in one of the chambers.

Ventilatory recordings. Respiratory measures were acquired continuously in the freely behaving animals using the barometric method (Buxco Electronics, Troy, NY; see Refs. 3 and 41). To minimize the long-term effect of signal drift resulting from temperature and pressure changes outside the chamber, a reference chamber of equal size in which temperature was measured using a T-type thermocouple was used. In addition, a correction factor was incorporated in the software routine to account for inspiratory and expiratory barometric asymmetries (12). At least 60 min before the start of each protocol, animals were allowed to acclimate to the chamber, in which humidified air (70–90% relative humidity) was passed through at a rate of 1–2 l/min as appropriate, using a precision-flow pump-reservoir system. Pressure changes in the chamber resulting from the inspiratory and expiratory temperature changes were measured using a high-gain differential pressure transducer (model MP45–1; Validyne). Analog signals were digitized continuously and analyzed on-line by a microcomputer software program (Buxco Electronics). A rejection algorithm was included in the breath-by-breath analysis routine and allowed for accurate rejection of motion-induced artifacts. It is important to point out that the time-decay characteristics of pressure signals may impact on the estimates of volume and that therefore the estimated volumes from our open plethysmographic technique represent qualitative estimates rather than true absolute values (51). T, respiratory frequency, and minute ventilation (E) were computed and then stored for subsequent off-line analysis. Peak HVR (pHVR) was defined as the maximal ventilatory output over three consecutive minutes during the hypoxic challenge, while hypoxic ventilatory decline (HVD) was defined as the nadir ventilation over three consecutive minutes. Hypoxic challenges consisted of 10% oxygen-balance nitrogen for 20 min.

Data analysis. All values are shown as means ± SE, unless indicated otherwise. Ventilatory measures were averaged at 1-min intervals and plotted. Analyses of variance were employed to compare differences in data. Significant comparisons were followed by Newman-Keuls post hoc tests. A P value <0.05 was considered to achieve statistical significance.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Twelve male PAFR(+/+) mice and 12 PAFR(–/–) mice derived from multiple litters were assessed in each experimental group for ventilatory recordings. Animals were studied longitudinally for the duration of the 30 days of IH beginning with day 0 at normoxia and subsequently at defined intervals (7, 14, and 30 days) during the course of the IH exposures. No significant differences between the groups emerged when ventilatory recordings were performed in normoxia at day 7; however, at days 14 and 30, PAFR(+/+) animals displayed a time-dependent increase in normoxic E similar to the long-term ventilatory facilitation (LTVF) induced by IH and previously observed in the rat (48). LTVF was attenuated markedly in PAFR(–/–) animals such that, relative to their baseline ventilatory pattern, PAFR(–/–) animals displayed no significant increase in normoxic E [Fig. 1A; P < 0.001 vs. PAFR(+/+) mice].



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1. Time course of normoxic minute ventilation (E; A), tidal volume (VT; B), and respiratory frequency (f; C) in platelet-activating factor receptor (PAFR)-sufficient [PAFR(+/+); {square}] and PAFR-deficient [PAFR(–/–); {bullet}] mice exposed to 30 days of intermittent hypoxia (IH). Measurements were taken before IH exposure (0d) and at defined intervals until 30 days of exposure (7d, 14d, and 30d). Normoxic E in PAF(–/–) was attenuated significantly at 14 and 30 days (P < 0.03 and P < 0.001, respectively). Differences at 30 days were primarily ascribable to significant differences in VT (P < 0.001).

 
At day 0, significant differences in E between the groups were noted during pHVR (P < 0.001, Fig. 2A) and HVD (P < 0.01, Fig. 2D), as previously reported (43). As previously reported, these differences were primarily accounted for by differences in VT in both pHVR and HVD (P < 0.02 and P < 0.03, respectively). However, these differences were no longer present at either 7, 14, or 30 days of IH exposures.



View larger version (29K):
[in this window]
[in a new window]
  		Fig. 2. Time course of peak hypoxic ventilatory response (pHVR) E (A), VT (B), and f (C) and hypoxic ventilatory decline (HVD) E (D), VT (E), and f (F) in PAFR(+/+) ({square}) and PAFR(–/–) ({bullet}) mice exposed to 30 days of IH. Measurements were taken before IH exposure (0d) and at defined intervals until 30 days of exposure (7d, 14d, and 30d). pHVR E and HVD in PAFR(–/–) were attenuated significantly only at 0 days compared with PAFR(+/+) (P < 0.001 and P < 0.01, respectively). Differences in E were primarily ascribable to significant differences in VT (P < 0.02 and P < 0.03, respectively); however, differences were no longer significant after 7 days of IH.

 
Closer examination of the data collected at 30 days of IH revealed that the significant differences between the PAFR(–/–) and PAFR(+/+) groups during normoxic E (Fig. 3A) were attributable to significant differences in VT (Fig. 3B) without significant changes in ventilatory frequency (Fig. 3C). However, in contrast with day 0, such group differences were not further present during the 20-min hypoxic challenges after 30 days of IH.



View larger version (23K):
[in this window]
[in a new window]
  		Fig. 3. Mean ± SE E (A), T (B), and f (C) in PAFR(+/+) ({square}) and PAFR(–/–) ({bullet}) mice exposed to 30 days of IH. Plots represent acute ventilatory challenges to 10% O2 for 20 min (n = 12/group). A: normoxic E facilitation was decreased in PAFR(–/–) (P < 0.001). B: differences were primarily ascribable to VT changes (P < 0.02) with no significant changes in f. No differences in pHVR or in HVD emerged.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study demonstrates that PAFR activity is necessary for emergence of the time-dependent increases in normoxic ventilation that occur after long-term exposures to IH in adult male mice (i.e., LTVF). In contrast, PAFR activity does not appear to play a role in other alterations of ventilatory patterning associated with long-term IH exposures such as the robust increases in the magnitude of pHVR and the attenuation of HVD (46, 48). Thus the absence of LTVF in PAFR(–/–) mice suggests that PAFR mediate intrinsic components of the neural plasticity of respiratory centers controlling normoxic ventilation.

The concept that PAF/PAFR activity is involved in neuronal plasticity is not novel and has been explored in several studies using tetanic stimulation-induced LTP as a model of neural plasticity. Pharmacological PAFR blockade attenuates LTP in the rat hippocampal CA1 and dentate gyrus, particularly in the medial perforant pathway (10, 23, 24) and in the medial vestibular nuclei (17). In addition, PAF administration has been shown to enhance excitatory postsynaptic responses (23, 24, 55) and to increase the frequency of spontaneous miniature excitatory postsynaptic potentials (11, 23) in hippocampal neurons. The functional relevance of these experiments was further demonstrated in behavioral studies conducted in a Morris water maze (39, 52). Rats received a unilateral intracaudate injection of mc-PAF (PAFR agonist) or BN-52021 (PAFR antagonist) immediately after training, and retention of the task was assessed 24 h later. Latencies to find the hidden platform in rats injected with mc-PAF were significantly lower than in vehicle controls, whereas the latencies of BN-52021-injected rats were significantly longer (52). Thus, in rostral brain structures, PAFR play a major role in synaptic plasticity phenomena that classically involve recruitment and activation of glutamatergic transmission.

The analogy between such rostral PAFR and glutamate receptor-dependent activity and plasticity and the brain stem is particularly striking in the nucleus of the solitary tract (nTS). Indeed, it is now well established that, within this brain stem region, glutamatergic pathways are required for normal neural transmission in HVR responses (34, 36, 37, 53) and are also activated in nTS plasticity (44). In addition, previous experiments from our laboratory confirmed the contributions of PAF-PAFR activation in HVR (16, 49). This study shows for the first time that long-term IH exposures induce sustained increases in normoxic ventilation in PAFR(+/+) mice (LTVF), and these changes may in fact represent a type of PAFR-dependent metaplasticity (for definition, please refer to Ref. 33) induced by the prolonged IH exposures. It is unclear whether LTVF is mediated by modification of peripheral chemoreceptor tonic activity (42, 44) or by alterations in the overall net neural output of central pattern ventilatory generators. This will require additional experiments, which are clearly beyond the scope of the present study.

Other studies using transgenic mice deficient in the dopamine D2 receptor have demonstrated impaired time-dependent adaptations to chronic sustained hypoxia (CH; see Refs. 18 and 19); however, we have previously shown that IH and CH are inherently different stimuli that produce unique ventilatory effects in rats (48). Despite such intrinsic differences between the two exposure paradigms, notable similarities also exist. Both exposures induce time-dependent increases in the baseline normoxic ventilation (LTVF) and time-dependent increases in pHVR, although the underlying mechanisms for each may differ (48). It is also noteworthy that, in certain models of plasticity, such as phrenic and ventilatory long-term facilitation elicited by a reduced number of recurrent hypoxic-normoxic cycles, the LTVF is undetectable after comparable durations of CH (1, 38). Furthermore, long-term IH exposures have been demonstrated to enhance the expression of both phrenic and ventilatory long-term facilitation in reduced, anesthetized preparations and in awake, freely behaving rats (29–31, 43, 48). Although the mechanism by which long-term IH exposures enhance LTVF remain unclear, evidence for the involvement of central serotoninergic receptors and brain-derived neurotrophic factor (2, 14, 15, 31) as well as involvement of reactive oxygen species (43) have recently emerged. Our findings now implicate the need for PAFR integrity to elicit LTVF after IH.

We should point out that the PAFR(–/–) mice used in these experiments were not conditional knockouts, i.e., the targeted gene ablation was not performed acutely in the adult animal, and therefore fetal ablation of PAFR may have allowed for adaptive mechanisms to be established. Therefore, if no differences in ventilatory responses had emerged between the two groups of mice studied herein, it could be argued that the absence of such differences in the ventilatory responses after long-term IH may reflect fetal cellular and molecular adaptations to PAFR deficiency. Although we cannot definitively rule out that such adaptive phenomena may have occurred, they were clearly insufficient to overcome the LTVF deficits incurred by the genetic ablation of PAFR. However, it can be postulated that the adaptive mechanisms that may underlie the IH-induced modification of both pHVR and HVD after long-term IH are PAFR-independent and do not require PAFR activity, even though PAFR activity is required for the normal expression of HVR in normoxic animals. These discrepancies in pHVR in normoxic and long-term intermittently hypoxic mice are not necessarily in conflict with the putative role of PAFR, given that mechanisms of adaptation required for survival in long-term IH may not be sufficiently induced by acute hypoxia and are thus not obvious in normoxic animals during hypoxic challenges. Similarly, inherent differences in PAFR(+/+) and PAFR(–/–) mice may be obscured by compensatory mechanisms that are PAFR independent and induced by long-term IH.

In summary, PAF has been implicated as playing an important role in the modulation of neural activity in general and in respiratory control in particular. The present study further substantiates that PAFR activation selectively mediates important components of the ventilatory response to hypoxia and is critically involved in metaplastic changes brought about by long-term intermittent hypoxic exposures.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institutes of Health (NIH) Grants HL-63912 and HL-69932 and The Commonwealth of Kentucky Research Challenge Trust Fund. S. R. Reeves was supported by NIH summer research stipend NCI R25 CA-44789.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. Gozal, Kosair Children's Hospital Research Institute, Univ. of Louisville, Suite 204, 570 South Preston St., Louisville, KY 40202 (E-mail: david.gozal{at}louisville.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. Baker TL and Mitchell GS. Episodic but not continuous hypoxia elicits long-term facilitation of phrenic motor output in rats. J Physiol 529: 215–219, 2000.
  2. Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, and Mitchell GS. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7: 48–55, 2004.
  3. Bartlett D Jr and Tenney SM. Control of breathing in experimental anemia. Respir Physiol 10: 384–395, 1970.
  4. Bazan NG, Zorumski CF, and Clark GD. The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J Lipid Mediators 6: 421–427, 1993.
  5. Benveniste J, Henson PM, and Cochrane CG. Leukocyte-dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet-activating factor. J Exp Med 136: 1356–1377, 1972.
  6. Bito H, Honda Z, Nakamura M, and Shimizu T. Cloning, expression and tissue distribution of rat platelet-activating-factor-receptor cDNA. Eur J Biochem 221: 211–218, 1994.
  7. Bito H, Kudo Y, and Shimizu T. Characterization of platelet-activating factor (PAF) receptor in the rat brain. J Lipid Mediators 6: 169–174, 1993.
  8. Bito H, Nakamura M, Honda Z, Izumi T, Iwatsubo T, Seyama Y, Ogura A, Kudo Y, and Shimizu T. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron 9: 285–294, 1992.
  9. Bussolino F, Gremo F, Tetta C, Pescarmona GP, and Camussi G. Production of platelet-activating factor by chick retina. J Biol Chem 261: 16502–16508, 1986.
  10. Chen C, Magee JC, Marcheselli V, Hardy M, and Bazan NG. Attenuated LTP in hippocampal dentate gyrus neurons of mice deficient in the PAF receptor. J Neurophysiol 85: 384–390, 2001.
  11. Clark GD, Happel LT, Zorumski CF, and Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 9: 1211–1216, 1992.
  12. Epstein RA, Epstein MA, Haddad GG, and Mellins RB. Practical implementation of the barometric method for measurement of tidal volume. J Appl Physiol 49: 1107–1115, 1980.
  13. Francescangeli E and Goracci G. The de novo biosynthesis of platelet-activating factor in rat brain. Biochem Biophys Res Commun 161: 107–112, 1989.
  14. Fuller DD, Bach KB, Baker TL, Kinkead R, and Mitchell GS. Long term facilitation of phrenic motor output. Respir Physiol 121: 135–146, 2000.
  15. Fuller DD, Zabka AG, Baker TL, and Mitchell GS. Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J Appl Physiol 90: 2001–2006, 2001.
  16. Gozal D, Holt GA, Graff GR, and Torres JE. Platelet-activating factor modulates cardiorespiratory responses in the conscious rat. Am J Physiol Regul Integr Comp Physiol 275: R604–R611, 1998.
  17. Grassi S, Francescangeli E, Goracci G, and Pettorossi VE. Role of platelet-activating factor in long-term potentiation of the rat medial vestibular nuclei. J Neurophysiol 79: 3266–3271, 1998.
  18. Huey KA, Low MJ, Kelly MA, Juarez R, Szewczak JM, and Powell FL. Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D(2) receptors. J Appl Physiol 89: 1142–1150, 2000.
  19. Huey KA, Szewczak JM, and Powell FL. Dopaminergic mechanisms of neural plasticity in respiratory control: transgenic approaches. Respir Physiol Neurobiol 135: 133–144, 2003.
  20. Ishii S, Kuwaki T, Nagase T, Maki K, Tashiro F, Sunaga S, Cao WH, Kume K, Fukuchi Y, Ikuta K, Miyazaki J, Kumada M, and Shimizu T. Impaired anaphylactic responses with intact sensitivity to endotoxin in mice lacking a platelet-activating factor receptor. J Exp Med 187: 1779–1788, 1998.
  21. Izquierdo I, Fin C, Schmitz PK, Da Silva RC, Jerusalinsky D, Quillfeldt JA, Ferreira MB, Medina JH, and Bazan NG. Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task. Proc Natl Acad Sci USA 92: 5047–5051, 1995.
  22. Izumi T and Shimizu T. Platelet-activating factor receptor: gene expression and signal transduction. Biochim Biophys Acta 1259: 317–333, 1995.
  23. Kato K, Clark GD, Bazan NG, and Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 367: 175–179, 1994.
  24. Kato K and Zorumski CF. Platelet-activating factor as a potential retrograde messenger. J Lipid Mediat Cell Signal 14: 341–348, 1996.
  25. Kondratskaya EL, Pankratov YV, Lalo UV, Chatterjee SS, and Krishtal OA. Inhibition of hippocampal LTP by ginkgolide B is mediated by its blocking action on PAF rather than glycine receptors. Neurochem Int 44: 171–177, 2004.
  26. Kornecki E and Ehrlich YH. Neuroregulatory and neuropathological actions of the ether-phospholipid platelet-activating factor. Science 240: 1792–1794, 1988.
  27. Kornecki E and Ehrlich YH. Calcium ion mobilization in neuronal cells induced by PAF. Lipids 26: 1243–1246, 1991.
  28. Kumar R, Harvey SA, Kester M, Hanahan DJ, and Olson MS. Production and effects of platelet-activating factor in the rat brain. Biochim Biophys Acta 963: 375–383, 1988.
  29. Ling L, Fuller DD, Bach KB, Kinkead R, Olson EB Jr, and Mitchell GS. Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing. J Neurosci 21: 5381–5388, 2001.
  30. McGuire M, Zhang Y, White DP, and Ling L. Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats. J Appl Physiol 93: 2155–2161, 2002.
  31. McGuire M, Zhang Y, White DP, and Ling L. Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol 95: 1499–1508, 2003.
  32. Medina JH and Izquierdo I. Retrograde messengers, long-term potentiation and memory. Brain Res Brain Res Rev 21: 185–194, 1995.
  33. Mitchell GS and Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol 94: 358–374, 2003.
  34. Mizusawa A, Ogawa H, Kikuchi Y, Hida W, Kurosawa H, Okabe S, Takishima T, and Shirato K. In vivo release of glutamate in nucleus tractus solitarii of the rat during hypoxia. J Physiol 478: 55–66, 1994.
  35. Mori M, Aihara M, Kume K, Hamanoue M, Kohsaka S, and Shimizu T. Predominant expression of platelet-activating factor receptor in the rat brain microglia. J Neurosci 16: 3590–3600, 1996.
  36. Ohtake PJ, Simakajornboon N, Fehniger MD, Xue YD, and Gozal D. N-methyl-D-aspartate receptor expression in the nucleus tractus solitarii and maturation of hypoxic ventilatory response in the rat. Am J Respir Crit Care Med 162: 1140–1147, 2000.
  37. Ohtake PJ, Torres JE, Gozal YM, Graff GR, and Gozal D. NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat. J Appl Physiol 84: 853–861, 1998.
  38. Olson EB Jr, Bohne CJ, Dwinell MR, Podolsky A, Vidruk EH, Fuller DD, Powell FL, and Mitchel GS. Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol 91: 709–716, 2001.
  39. Packard MG, Teather LA, and Bazan NG. Effects of intrastriatal injections of platelet-activating factor and the PAF antagonist BN 52021 on memory. Neurobiol Learn Mem 66: 176–182, 1996.
  40. Panetta T, Marcheselli VL, Braquet P, and Bazan NG. Arachidonic acid metabolism and cerebral blood flow in the normal, ischemic, and reperfused gerbil brain. Inhibition of ischemia-reperfusion-induced cerebral injury by a platelet-activating factor antagonist (BN 52021). Ann NY Acad Sci 559: 340–351, 1989.
  41. Pappenheimer JR. Sleep and respiration of rats during hypoxia. J Physiol 266: 191–207, 1977.
  42. Peng YJ, Overholt JL, Kline D, Kumar GK, and Prabhakar NR. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci USA 100: 10073–10078, 2003.
  43. Peng YJ and Prabhakar NR. Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia. J Appl Physiol 94: 2342–2349, 2003.
  44. Peng YJ and Prabhakar NR. Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96: 1236–1242, 2004.
  45. Poon CS and Siniaia MS. Plasticity of cardiorespiratory neural processing: classification and computational functions. Respir Physiol 122: 83–109, 2000.
  46. Prabhakar NR and Kline DD. Ventilatory changes during intermittent hypoxia: importance of pattern and duration. High Alt Med Biol 3: 195–204, 2002.
  47. Prehn JH and Krieglstein J. Platelet-activating factor antagonists reduce excitotoxic damage in cultured neurons from embryonic chick telencephalon and protect the rat hippocampus and neocortex from ischemic injury in vivo. J Neurosci Res 34: 179–188, 1993.
  48. Reeves SR, Gozal E, Guo SZ, Sachleben LR Jr, Brittian KR, Lipton AJ, and Gozal D. Effect of long-term intermittent and sustained hypoxia on hypoxic ventilatory and metabolic responses in the adult rat. J Appl Physiol 95: 1767–1774, 2003.
  49. Simakajornboon N, Graff GR, Torres JE, and Gozal D. Modulation of hypoxic ventilatory response by systemic platelet-activating factor receptor antagonist in the rat. Respir Physiol 114: 213–225, 1998.
  50. Sogos V, Bussolino F, Pilia E, Torelli S, and Gremo F. Acetylcholine-induced production of platelet-activating factor by human fetal brain cells in culture. J Neurosci Res 27: 706–711, 1990.
  51. Szewczak JM and Powell FL. Open-flow plethysmography with pressure-decay compensation. Respir Physiol Neurobiol 134: 57–67, 2003.
  52. Teather LA, Packard MG, and Bazan NG. Effects of posttraining intrahippocampal injections of platelet-activating factor and PAF antagonists on memory. Neurobiol Learn Mem 70: 349–363, 1998.
  53. Vardhan A, Kachroo A, and Sapru HN. Excitatory amino acid receptors in commissural nucleus of the NTS mediate carotid chemoreceptor responses. Am J Physiol Regul Integr Comp Physiol 264: R41–R50, 1993.
  54. Waters KA and Gozal D. Responses to hypoxia during early development. Respir Physiol Neurobiol 136: 115–129, 2003.
  55. Wieraszko A, Li G, Kornecki E, Hogan MV, and Ehrlich YH. Long-term potentiation in the hippocampus induced by platelet-activating factor. Neuron 10: 553–557, 1993.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/2/R369    most recent
00128.2004v1
Right arrow Alert me when this article is cited
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 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 Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Reeves, S. R.
Right arrow Articles by Gozal, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Reeves, S. R.
Right arrow Articles by Gozal, D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.