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Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794-8661
Submitted 20 October 2003 ; accepted in final form 17 December 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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respiratory rhythm generation; central hypoxic chemosensitivity; glutamate receptors; neural control of breathing
With respect to neuronal excitation as a possible mechanism, we have proposed that hypoxia itself may initiate the response by directly exciting hypoxia-chemosensitive neurons (25, 28). In support of direct hypoxic excitation, recent studies have shown hypoxic chemosensitivity in the pre-BötC both in vivo (26, 28) and in vitro (16, 32, 33), including the demonstration that focal hypoxia in this region elicits excitation of phrenic nerve discharge, including a gasplike discharge pattern (28). Within a neural network, however, other potential mechanisms for neuronal excitation must be considered. Because hypoxia has been reported to enhance glutamate release in some regions of the brain (10, 15, 19, 20), centrally mediated hypoxic respiratory excitation may alternatively result from transynaptic mechanisms involving excitation via activation of glutamate [i.e., excitatory amino acid (EAA)] receptors. Support for a glutamate-mediated effect in the production of gasping comes from the demonstration that activation of ionotropic EAA receptors in the pre-BötC can shift the eupneic pattern of phrenic nerve discharge to a gasplike discharge pattern, although this modulation was shown under hyperoxic conditions (27).
To date, a limited number of studies have explored a potential role for activation of ionotropic EAA receptors in the production of hypoxia-induced gasping (4, 8). These studies have demonstrated that, in older neonatal (e.g., 15-day-old) and adult mammals, systemic administration of either N-methyl-D-aspartate (NMDA) or non-NMDA (i.e., ionotropic EAA receptor subtypes) receptor antagonists is ineffective in altering gasping produced by carbon monoxide (CO) and anoxia. Hypoxia-induced gasping, however, can be modified by afferent inputs (14), many of which utilize EAA neurotransmission. Furthermore, recent work from our laboratory has demonstrated that activation of ionotropic EAA receptors in the pre-BötC, using DL-homocysteic acid (DLH), which activates both NMDA and non-NMDA receptors, elicits frequency modulation of not only eupneic bursts (27) but also hypoxia-induced gasps (26). Thus one possible explanation for the observations in the above studies (4, 8) is that no attempt was made to simultaneously block both ionotropic EAA receptor subtypes.
The present study was, therefore, undertaken to determine whether activation of ionotropic EAA receptors in the pre-BötC participates in the production and/or expression of gasping evoked in response to severe brain hypoxia. Because we believe that hypoxia-induced gasping is produced, at least in part, by direct hypoxic excitation in the pre-BötC (i.e., intrinsic hypoxic chemosensitivity), we hypothesized that activation of ionotropic EAA receptors in this region would not be required for the production of hypoxia-induced gasping. Furthermore, because we have previously demonstrated that activation of ionotropic EAA receptors in the pre-BötC enhances the frequency of hypoxia-induced gasps (26), we further hypothesized that activation of ionotropic EAA receptors in this region would play a modulatory role in the expression hypoxia-induced gasping.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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In brief, anesthesia was induced in adult cats (2.8-3.3 kg; n = 11) with halothane (5%) in O2 and maintained with intravenous 
-chloralose (initial 35-50 mg/kg; supplemental 3-5 mg/kg). The adequacy of anesthesia was regularly verified by absence of a withdrawal reflex (in the unparalyzed state) or blood pressure response (during muscular paralysis) to a noxious paw pinch. The right brachial vein and both brachial arteries were cannulated for administration of drugs, measurement of arterial blood pressure (Statham transducer, P23XL), and sampling of arterial blood. The trachea was cannulated, the vagus nerves and carotid sinus nerves were transected bilaterally, and the lungs were mechanically ventilated with 40% O2 in a balance of N2. The cat was then paralyzed with vecuronium bromide (0.2-0.4 mg/kg iv), supplemented as needed. The dorsal surface of the brain stem was exposed, and the C5 rootlet of one or both phrenic nerves was isolated for recording.
Experimental protocol. We examined the effects of blockade of ionotropic EAA receptors in pre-BötC on the patterning, timing, and frequency of phrenic nerve discharge during hypoxia-induced gasping. Blockade of ionotropic EAA receptors was produced by bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (Kyn; 20-100 mM; 40 nl; n = 8) into the pre-BötC. Sites in the pre-BötC were initially functionally identified by use of microinjection DLH (10 mM; 10-20 nl) under hyperoxic conditions, as previously described (27), and all microinjections into the medulla were made with the use of a triple-barreled glass pipette (12- to 20-µm tip diameter) attached to a pressure injection device (General Valve Picospritzer II). In all experiments, gasping was produced by lowering the fractional concentration of O2 in the inspired gas mixture to 6% O2 in a balance of N2 for 3-6 min. An initial response to the hypoxic exposure was obtained, the cat was allowed to recover from the hypoxic challenge for at least 30 min, and then Kyn was microinjected into the pre-BötC. In five experiments, Kyn was microinjected into the pre-BötC on one side followed within 3-5 min by microinjection of Kyn into the contralateral pre-BötC. In the remaining three experiments, Kyn was microinjected into the pre-BötC on one side, 
10-15 min was allowed for the antagonist to exert its effects, and then DLH (20 nl) was microinjected into the same site in the pre-BötC to confirm that Kyn blocked ionotropic EAA receptors in this region. Approximately 3-5 min after this DLH challenge, Kyn was microinjected into the contralateral pre-BötC. In all experiments, at least 10 min were allowed for the antagonist to exert its effects after bilateral microinjection, and then the hypoxic exposure was repeated. In three of the above experiments, at 90 min after bilateral microinjection of Kyn into the pre-BötC (when phrenic nerve discharge appeared to have recovered from blockade of ionotropic EAA receptors in this region), an additional hypoxic exposure was performed (i.e., recovery). In three additional cats, control experiments were conducted with the use of saline (vehicle) instead of Kyn microinjection. The microinjection protocol used for these experiments was similar to the first protocol described above. Before the hypoxic exposure and at the onset of gasping, whenever possible, an arterial blood sample was obtained for measurement of PO2, PCO2, pH, and arterial O2 saturation (SaO2) and content (CaO2) (Radiometer ABL-500/OSM3). It should be noted that the OSM 3 has a special mode for measurements of hemoglobin concentration and its derivatives on 10 types (species) of animal blood samples; the animal mode settings for cat (animal mode 6) were used in the present experiments. In addition, the onset latency for the production of hypoxia-induced gasping was measured. At the end of each experiment, fast green dye (2%; 
120 nl) was microinjected to mark the injection sites, the brain stem was removed, and the tissue was processed for histological analysis and verification of the location of the injection sites (Fig. 1B) as previously described (27, 28).
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Histology. In brief, after immersion fixation of the brain stem in 4% Formalin for at least 48 h, the brain stem was frozen and sectioned coronally (40-µm thickness) using a cryostat (Leica model CM1850). All tissue sections were mounted directly on slides in two separate sets (alternating sections), and one set of slides was stained for cell bodies by use of 1% neutral red dye. Tissue sections containing sites marked with fast green dye (usually 3-5 tissue sections per brain stem) were examined with an Olympus BH-2 microscope, and drawings of these tissue sections were made with the aid of a Ken-a-Vision microprojector.
Data analysis. For hypoxia-induced gasping, the peak amplitude of integrated phrenic nerve discharge, gasp duration (TI), duration between gasps (TE), gasp frequency, and onset latency to the first gasp were determined before and after blockade of ionotropic EAA receptors in the pre-BötC. Amplitude is reported as a percentage of the maximal gasp amplitude observed in each cat. All hypoxia-induced gasps under both conditions were used for these analyses, and data are reported as means ± SE. Student's paired t-tests or the paired nonparametric Wilcoxon's signed-rank test, as appropriate, was used to determine statistical significance, for which the criterion level was set at P < 0.05. Statistical analyses were not conducted on recovery data because of the small sample size (n = 3). In addition to analyses on hypoxia-induced gasps, similar measurements were obtained on basal phrenic nerve discharge before and after microinjection of Kyn to evaluate the effects of blockade of ionotropic EAA receptors in the pre-BötC under hyperoxic conditions.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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40-60 min after completion of the bilateral microinjection. The initial reduction of phrenic burst frequency was mediated predominantly by a prolongation of TE (P < 0.05) although, in most experiments, TI was also slightly increased (P < 0.05). In addition, in some experiments, spurious discharges of action potentials or a low level of tonic basal firing could be seen after bilateral blockade of ionotropic EAA receptors in the pre-BötC. An example showing the effects of bilateral blockade of ionotropic EAA receptors in the pre-BötC on phrenic nerve discharge is shown in Fig. 1. As can be seen in this example, within only a few minutes after bilateral microinjection of Kyn into the pre-BötC, phasic phrenic nerve activity was substantially reduced, and by 10 min, phasic phrenic nerve activity was abolished. A similar time course for the onset of the Kyn-induced effects was observed in most of the experiments; however, when microinjection into the contralateral pre-BötC was delayed (in 3 experiments described in Experimental protocol), apnea occurred within 1-2 min after completion of the bilateral microinjection. It should be noted that, in these three experiments, a substantial reduction in the amplitude and frequency of phasic phrenic bursts was observed after unilateral microinjection of Kyn into the pre-BötC (see Fig. 2B for an example). Also shown in Fig. 1 is the distribution of pre-BötC sites into which Kyn was microinjected. Our histological analyses confirmed that all microinjection sites functionally identified as the pre-BötC were located within the anatomical boundaries described for the pre-BötC in adult cat (5, 17, 22, 27). Furthermore, these analyses revealed no differences in the location of injection sites for the two microinjection protocols used.
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Confirmation of blockade of ionotropic EAA receptors by Kyn. To confirm that Kyn blocked ionotropic EAA receptors in the pre-BötC, in three experiments, phrenic nerve discharge was examined in response to DLH microinjection 10-15 min after microinjection of Kyn into the same site in the pre-BötC. Although microinjection of DLH into the pre-BötC before blockade of ionotropic EAA receptors elicited either phasic (n = 1) or tonic (n = 2) excitation of phrenic nerve discharge [as previously described (Refs. 26, 27)], similar microinjection of DLH after blockade of ionotropic EAA receptors was ineffective in altering the Kyn-induced pattern of phrenic nerve activity in each of these experiments. An example showing the effects of blockade of ionotropic EAA receptors in the pre-BötC on the DLH-induced excitation of phrenic nerve discharge is shown in Fig. 2. In this example, tonic excitation of phrenic nerve discharge was elicited by microinjection of DLH into the pre-BötC before microinjection of Kyn; however, 10 min after microinjection of Kyn, similar microinjection of DLH no longer elicited excitation of phrenic nerve discharge.
Characteristics of hypoxia-induced gasping before Kyn. In each of the experiments conducted, lowering the fractional concentration of O2 in the inspired gas from 40 to 6% O2 (in a balance of N2) produced gasping within 3 min (mean ± SE = 146 ± 11 s; range = 103-184 s). Hypoxia-induced gasping was characterized by abrupt-onset, high-amplitude, short-duration bursts of phrenic nerve activity (Fig. 3A), which exhibited a decrementing discharge pattern (Fig. 4A, Baseline). Gasps were separated by longer periods of phrenic silence (i.e., TE) than those associated with the eupneic burst pattern recorded under hyperoxic conditions, and 2-8 gasps/min were observed. In total, 55 gasps were recorded under these conditions. SaO2 and CaO2 at the onset of gasping (and immediately preceding the hypoxic challenge) are provided in Table 1.
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Effects of Kyn on hypoxia-induced gasping. Although bilateral microinjection of Kyn into the pre-BötC eliminated basal phrenic nerve discharge, lowering the fractional concentration of O2 in the inspired gas from 40 to 6% O2 (in a balance of N2) still produced gasping. Under these conditions, hypoxia-induced gasping was similarly characterized by abrupt-onset, high-amplitude, short-duration bursts of phrenic nerve activity (Fig. 3B), which exhibited a decrementing discharge pattern (Fig. 4A, Kyn); however, the onset latency to gasping, the number of gasps during the hypoxic gas exposure, and the duration of gasps were significantly altered. Under these conditions, the onset latency to gasping was increased by 13 ± 3 s (P < 0.05; n = 8), although in two of these experiments, little (i.e., 4.5 s) or no change in onset latency was observed; in the remaining six experiments, the increase in onset latency ranged from 14 to 21 s. This increase in onset latency to gasping resulted in a slight, but not significant, reduction in both SaO2 and CaO2 at the onset of gasping (P 
0.1; Table 1). Under these conditions, the number of gasps was reduced for the same duration of hypoxic gas exposure (P < 0.05), and a total of 30 gasps were recorded. The resulting reduction in gasp frequency was produced predominantly by a significant increase in the duration between gasps (TE; P < 0.05), although a significant increase in gasp TI was also observed (P < 0.05). In addition, the amplitude of gasps was slightly reduced, although these differences were not statistically significant (P = 0.08). Summary data showing the effects of blockade of ionotropic EAA receptors in the pre-BötC on the characteristics of hypoxia-induced gasping are provided in Fig. 4B.
Hypoxia-induced gasping after recovery from Kyn. In three experiments, we examined hypoxia-induced gasping after recovery from Kyn. Under these conditions, lowering the fractional concentration of O2 in the inspired gas from 40 to 6% O2 (in a balance of N2) produced gasping, which exhibited similar timing and patterning characteristics to those observed under baseline conditions. Furthermore, the onset latency to gasping was similar for the baseline and recovery hypoxic challenges (mean ± SE = 146 ± 7 vs. 145 ± 6 s, respectively), and totals of 13 and 14 gasps were recorded for the baseline and recovery hypoxic challenges, respectively. Summary data for the characteristics of hypoxia-induced gasping for these recovery experiments are included in Fig. 4B.
Control experiments. In three experiments in which saline, instead of Kyn, was microinjected into the pre-BötC, lowering the fractional concentration of O2 in the inspired gas from 40 to 6% O2 (in a balance of N2) produced gasping that exhibited characteristics similar to those observed during the initial hypoxic gas exposure. In these experiments, the onset latency to gasping was 147 ± 10 and 144 ± 11 s in the first and second hypoxic challenges, respectively, and a similar number of gasps were observed in both trials for each control experiment (e.g., in control experiment 1, 4 gasps were observed during each hypoxic challenge). Furthermore, no differences were noted in the hypoxia-induced gasp discharge pattern (i.e., shape, peak amplitude), gasp TI, or the duration between gasps between the first and second hypoxic challenges (not shown).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Although the primary purpose of the present study was to investigate whether activation of ionotropic EAA receptors in the pre-BötC plays a role of in production and/or expression of hypoxia-induced gasping, we also observed that blockade of ionotropic EAA receptors in this region eliminated phasic phrenic nerve discharge. This observation is consistent with previous in vivo findings in anesthetized cat demonstrating that antagonism of NMDA and non-NMDA receptors in the ventrolateral medulla [presumably in a region corresponding to the rostral ventral respiratory group (VRG) and pre-BötC] produces a progressive reduction in breathing that progressed to apnea (1), and in vitro findings in transverse medullary slices obtained from neonatal rat demonstrating that blockade of non-NMDA receptors in the pre-BötC eliminates respiratory rhythm (6) and synchronized inspiratory neuronal activities (11), although our data provide no insight into whether the present observations reflect an effect of blockade of NMDA receptors, non-NMDA receptors, or the simultaneous blockade of both receptors subtypes. We believe that our present observations provide additional evidence for a role of ionotropic EAA receptors in the in vivo pre-BötC in respiratory rhythm generation; however, it should be noted that these observations were made under hyperoxic, normocapnic conditions and therefore represent the effects of blockade of ionotropic EAA receptors in the pre-BötC on basal phrenic nerve discharge. We did not examine whether the apnea produced in these experiments could have been reversed by increasing respiratory network drive (i.e., hypercapnia), nor did we investigate the effects of blockade of ionotropic EAA receptors in this region during increased respiratory network drive (i.e., hypercapnia); thus further investigation will be required to evaluate the role of ionotropic EAA receptors in this region under conditions involving increased respiratory network drive on phasic phrenic nerve discharge.
The present investigation does not resolve or even address whether the pre-BötC is the "gasping center." Recent studies, including work from our laboratory, have suggested that the pre-BötC plays a role, not only in the generation and modulation of eupneic breathing, but also in the production and/or expression of gasping (12, 26, 28). With this in mind, our present experiments were designed to investigate whether activation of ionotropic EAA receptors in the pre-BötC is required for the production and/or expression of gasping in response to severe brain hypoxia, not whether this region is required for the generation of hypoxia-induced gasping. Thus our present observations only suggest that activation of ionotropic EAA receptors in the pre-BötC is not required for, but may play a modulatory role in, the production of hypoxia-induced gasping; they do not exclude a role for this region in the genesis of hypoxia-induced gasping nor do they implicate or exclude a role for other respiratory areas outside of the pre-BötC in the genesis of hypoxia-induced gasping. Our findings also provide additional support for the participation of this region in the generation and modulation of the eupneic pattern of inspiratory motor output.
In the present investigation, we bilaterally microinjected Kyn into the pre-BötC to block ionotropic EAA receptors. We believe that these injections were effective in producing complete, not partial, blockade of ionotropic EAA receptors because microinjection of the ionotropic glutamate agonist DLH into the pre-BötC after Kyn was ineffective in altering phrenic nerve discharge. The volumes of injectate, however, were not identical. In all experiments, the volume of Kyn microinjected into the pre-BötC (on each side) was 40 nl, which was twice the volume of DLH used to confirm the effectiveness of blockade. This volume (for Kyn) was selected to maximize the extent of the pre-BötC affected by this agent without spreading substantially to adjacent regions. The volume of DLH selected corresponds to the maximal volume that we have used previously for functionally identifying the pre-BötC (26-28). We are confident, however, that our present findings represent the effects of blockade of ionotropic EAA receptors in the pre-BötC on basal phrenic nerve discharge and hypoxia-induced gasping and do not reflect the effects of spread of injectate to adjacent respiratory-related areas because blockade of ionotropic EAA receptors in the adjacent inspiratory portion of the rostral VRG (located caudal to the pre-BötC) has been shown to produce respiratory excitation [although preceded by a transient (30 s) apnea] in decerebrate cat (2).
Role of the pre-BötC in hypoxia-induced gasping. As noted above, our present observations suggest that activation of ionotropic EAA receptors in the pre-BötC is not required for the production of hypoxia-induced gasping. Two possible explanations are conceivable: 1) hypoxia-induced gasping could persist after blockade of ionotropic EAA receptors in the pre-BötC because other unaffected regions may be sufficient to generate gasping, albeit at a slower rate with a longer burst duration, after respiratory rhythm generation has been blocked in the pre-BötC. This other region(s) could be less hypoxia sensitive than the pre-BötC, thus explaining the delay in the onset of gasping. 2) Hypoxia-induced gasping could persist after the blockade of ionotropic EAA receptors in the pre-BötC because other neural mechanism(s) may be involved. For example, both GABAA-mediated disinhibition and focal hypoxia in the pre-BötC during hyperoxia have been shown to elicit a gasplike pattern of phrenic nerve discharge in vivo (25, 28, 29), and exposure of the in vitro transverse medullary slice, which includes the pre-BötC, to anoxia has been demonstrated to reduce synaptic inhibition leading to production of decrementing inspiratory neuronal activities and gasping (12). Thus disinhibition and/or direct hypoxic excitation may be neural mechanisms implemented in the pre-BötC in response to severe brain hypoxia, resulting in the production of gasping. Alternatively, glutamate may participate in the production of gasping by acting on metabotropic, and not ionotropic, receptors. Furthermore, severe hypoxia is known to produce complex changes in the release of both excitatory and inhibitory neurotransmitters and neuromodulators in some brain regions, including brain stem regions associated with respiratory control (3, 7, 9, 13, 19, 30, 34, 35); thus other excitatory neurotransmitters and/or neuromodulators (e.g., substance P; nitric oxide) in this region may participate in the production of hypoxia-induced gasping. Further investigation is required to assess these possibilities.
Although activation of ionotropic EAA receptors in the pre-BötC does not appear to be essential for the genesis of hypoxia-induced gasping, it seems to play a modulatory role in the expression of gasping. This observation was not unexpected because focal activation of ionotropic EAA receptors during hypoxia-induced gasping enhances the frequency of gasps (26), afferent input utilizing glutamatergic neurotransmission (21, 36) produces premature gasps (14), and severe hypoxia is well known to increase the release of glutamate in some regions of the brain (10, 15, 20), including the VRG (19). Although the duration between gasps was significantly prolonged, as would have been predicted on the basis of our previous observations (26) and those of Melton et al. (14), our present investigation also demonstrated that blockade of ionotropic EAA receptors in this region significantly increased (by 30%) gasp duration. This observation was somewhat surprising because, in our previous experiments, activation of ionotropic EAA receptors in the pre-BötC during hypoxia-induced gasping exerted little if any reduction (10%) in gasp burst duration (26). We interpret this observation to indicate that glutamate acting via ionotropic EAA receptors may play a role in synchronizing inspiratory activities in this region during gasping in a manner similar to that required for respiratory rhythm generation in vitro (11, 33). Our present experiments, however, do not provide any insight into whether the modulatory role played by activation of ionotropic EAA receptors is via NMDA or non-NMDA receptors. Furthermore, the present observations suggest that neural mechanisms other than activation of ionotropic EAA receptors in the pre-BötC must also participate in synchronizing inspiratory activities in this region because hypoxia-induced gasps exhibit similar patterning characteristics (i.e., shape and amplitude of bursts) both before and after blockade of pre-BötC ionotropic EAA receptors. Another interesting and unexpected observation in the present investigation is that blockade of ionotropic EAA receptors in the pre-BötC significantly increased the onset latency to gasping. The significance of this observation is unclear; however, it may indicate that activation of ionotropic EAA receptors during severe hypoxia is required for shifting the balance between excitation and inhibition in this region in favor of neuronal excitation for the initiation of gasping.
The interpretations provided above are based on the underlying assumption that the pre-BötC plays a role in the production and/or expression of gasping (12, 26, 28). This assumption does not exclude potential contributions from respiratory areas outside of the pre-BötC in the hypoxia-induced gasping response, and, therefore, an additional explanation for our present observations must also be considered to take into account that the in vivo pre-BötC may only be part of the network responsible for the genesis of hypoxia-induced gasping. If we consider that the respiratory network generating gasping in response to severe brain hypoxia includes (but is not exclusively dependent on) the pre-BötC, inactivation of this region by blockade of ionotropic EAA receptors would reduce the overall excitability of the gasping network. Under these conditions, excitation of respiratory areas outside the pre-BötC would generate gasping; however, the onset to gasping would be delayed and gasping would be modified (i.e., longer TI and slower gasp frequency) because the excitation normally provided by the pre-BötC is absent. Although we cannot exclude this possibility, we also cannot exclude the possibility that mechanisms other than activation of ionotropic EAA receptors in the pre-BötC participate in the genesis of hypoxia-induced gasping.
Role of ionotropic EAA receptors in hypoxia-induced gasping: comparison to other studies. Our present observations suggest a modulatory role for ionotropic EAA receptor activation in the pre-BötC in hypoxia-induced gasping in anesthetized adult cat. This observation appears to be in contrast to previous observations by Chae et al. (4), in which they reported that gasping activity is unaffected by ionotropic EAA receptor blockade in the same animal model. There are a number of possible explanations for this discrepancy. Among these, Chae and colleagues blocked ionotropic EAA receptors using systemic administration of either NMDA or non-NMDA receptor antagonists, and they used CO, instead of hypoxic gas, to elicit hypoxia-induced gasping. In our experiments, we targeted the pre-BötC and evaluated the effects of simultaneous blockade of both receptor subtypes on hypoxic hypoxia-induced gasping. Thus differences between our present observations and their findings might reflect an effect of combined blockade of NMDA and non-NMDA receptors, access of antagonists to the pre-BötC (or additional influences from other sites in their study), and/or differences in the neural mechanism(s) that may be invoked to produce gasping in response to hypoxia vs. CO. It is unclear, however, which if any of these possibilities are responsible for the differences between the observations of the study by Chae and colleagues and our present investigation.
Our present observation is also, in part, in contrast to previous observations by Gozal and Torres (8), in which they demonstrated that systemic administration of a NMDA receptor antagonist is ineffective in altering the onset latency to gasping or pattern of gasping produced by anoxia in 15-day-old rats, although the onset latency to gasping under these conditions is delayed in 2- to 10-day-old rats. Their study suggests that NMDA receptors may participate in hypoxia-induced gasping, but this influence appears to be developmentally regulated. Thus the findings of Gozal and Torres in conjunction with our present observations may indicate that activation of NMDA receptors plays a modulatory role in hypoxia-induced gasping in young neonatal mammals but activation of both NMDA and non-NMDA receptors may be required for this modulation in older neonatal and adult mammals. We cannot, however, exclude the possibility of species differences in these observations.
In summary, our results indicate that activation of ionotropic EAA receptors in the pre-BötC is not essential for the production of hypoxia-induced gasping, although generation of eupneic inspiratory motor output appears to be dependent on such activation. Furthermore, although hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in this region, ionotropic EAA receptor activation appears to play a modulatory role in the expression of the hypoxia-induced response, by modifying the onset latency to and frequency of hypoxia-induced gasps. On the basis of these observations, we conclude that activation of ionotropic EAA receptors in the pre-BötC participates not only in the generation and modulation of eupneic breathing but also in the modulation of hypoxia-induced gasping. Additionally, the present findings provide further support for the pre-BötC as the primary locus of respiratory rhythm generation in vivo.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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This article has been cited by other articles:
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  I. C. Solomon Glutamate Neurotransmission Is Not Required for, But May Modulate, Hypoxic Sensitivity of Pre-Botzinger Complex In Vivo J Neurophysiol, March 1, 2005; 93(3): 1278 - 1284. [Abstract] [Full Text] [PDF]
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