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Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
Submitted 21 January 2003 ; accepted in final form 16 June 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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respiration; plasticity; conscious rats
In a previous study conducted on anesthetized, paralyzed, vagotomized, and ventilated rats, it was found that pretreatment with CIH (5 min 11-12% O2/5 min air, 12 h/night, 7 nights) greatly enhanced both the acute hypoxic phrenic response and the phrenic LTF elicited subsequently by AIH (20). This anesthetized preparation has many advantages, e.g., blood gases and body temperature can be continuously monitored and well controlled, and possible CIH effects on pulmonary mechanics can be excluded. However, in these experiments the critical baseline of the phrenic nerve activity was artificially set at an end-tidal CO2 partial pressure 3 Torr above the CO2-apneic threshold, and the average threshold was 6 Torr lower in CIH-treated vs. untreated control rats (20). This threshold difference could potentially confound the assessment of both the short-term hypoxic phrenic response and phrenic LTF because both are expressed as values normalized to baseline and the input-output of phrenic responses to chemoreceptor activation is not linear (8). A stimulus usually produces a larger phrenic response if the baseline level is set lower.
In addition, because LTF data were only collected 
8 h after CIH treatment, the persistence of the CIH effect on LTF was not adequately investigated. Thus the objective of the present study was to examine the effect of CIH on ventilatory LTF and to determine the persistence period of this CIH effect in conscious, freely behaving rats. We hypothesized that CIH would enhance both the magnitude and duration of ventilatory LTF and that this CIH effect on LTF can last for several days.
A portion of this work has appeared in abstract form (27).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Ventilatory and Metabolic Measurements
Respiratory ventilation and metabolic rate were measured by use of a custom-made 3-liter whole-body flow-through plethysmograph (Buxco Electronics, Sharon, CT). Individual unanesthetized and unrestrained rats were placed in the precalibrated plethysmographic chamber connected via a controlled leak to a reference chamber. The atmosphere within the animal chamber was maintained with air flowing through the chamber at a rate of 3 l/min. A bias flow was connected to an aerosol port of the chamber to maintain the O2 concentration within the unit. A custom-made computer software system (Biosystem XA, Buxco Electronics) monitored the output of a differential pressure transducer (TRD5100) connected between the animal and reference chambers. This software system provides a breath-by-breath display of breathing frequency (fR), tidal volume (VL), minute ventilation (
E), inspiratory time (TI), and expiratory time (TE) before, during, and after AIH used to evoke LTF.
The computer also continuously monitored the output of the CO2 and O2 (Servomex Transducers, Norwood, MA) analyzer, sensing alternately inspired and expired gases. With the known flow rate, the measurements of the CO2 and O2 gas concentration were used to determine the CO2 production (CO2) that defines metabolic rate and O2 consumption (O2) in the present study. Body temperature was measured before and immediately after the experiment by using a rectal thermometer.
CIH
Rats were housed in normal rat cages and were given food and water ad libitum. These cages were placed into a custom-made Plexiglas chamber. This chamber was flushed with alternating mixtures of N2, O2, and air to achieve quasisquare wave intermittent hypoxia of 11-12% O2 for 5 min and normoxia for 5 min. It took 30 s for the O2 to drop to the targeted 11% and 30 s to return to 21%. Gas mixtures were flushed at a rate sufficient to maintain chamber CO2 levels below 0.5%. This intermittent hypoxia was repeated for 12 h a night (from 6:00 PM to 6:00 AM, when rats are in their active period) for 7 consecutive nights. The chamber was flushed with air or open to room air during the remaining 12 h each day. The temperature in the chamber was maintained between 20 and 22°C.
General Experimental Procedures
Rats were placed in the plethysmographic chamber and allowed to adapt to the chamber for 1 h. Baseline (resting E) was then measured over 10 min, and E was continuously monitored throughout the AIH stimulus protocols. During this period, rats were exposed to 5 min of poikilocapnic hypoxia (12% O2) followed by 5 min of air. This cycle was repeated to achieve the episode number in the particular protocol. In the animal chamber, the shift from normoxia to the target hypoxia level (12% O2) took less than 1 min, and the shift from hypoxia to normoxia took less than 30 s. During these hypoxic and normoxic episodes, only the final 2-min data of each episode were averaged and included in the analysis. The hypoxic ventilatory response (HVR) is defined as an increase from baseline to hypoxic E, normalized to a percentage of the baseline. After the last hypoxia episode, Ewas measured at 15-min intervals (i.e., 15, 30, 45, 60, 75, and 90 min), with each value representing a 5-min average (e.g., the 30-min posthypoxia value is an average of the data collected between 30 and 35 min). Ventilatory LTF is defined as an increase from baseline in posthypoxia E, normalized to a percentage of the baseline.
AIH
Protocol 1. Rats (n = 7) were exposed to five episodes of 5 min of poikilocapnic hypoxia (12% O2), interspersed with 5-min intervals of normoxia. E was measured before, during, and up to 90 min after AIH to determine resting E, HVR, and ventilatory LTF, respectively. This protocol was repeated four times on the same rats, before and at 8 h, 3 days, and 7 days after CIH treatment. Data were always collected at the same time of day (2:00 PM) for each measurement.
Protocol 2. Rats (n = 7) were exposed to 10 episodes of 5 min 12% O2 with 5-min normoxic intervals to evoke ventilatory LTF. E was also measured before, during, and up to 90 min after AIH. This protocol was also repeated four times on the same rats at the same time of day (2:00 PM).
Metabolic Rate
Metabolic rate (CO2) and O2 consumption (O2) were measured before (baseline) and after the AIH stimulus protocol in each experiment. This measurement was also repeated four times on the same rats, before and at 8 h, 3 days, and 7 days after CIH treatment. However, CO2 and O2 were not measured during AIH.
Blood-Gas Measurements
These measurements were carried out in a separate group of rats (n = 3). The implantation of the blood sampling catheter and the body temperature transmitter has been previously described (28). Briefly, 1 wk before any measurement, catheters were placed into the descending aorta via the femoral artery under isoflurane inhalation anesthesia. The catheters were routed under the skin to the back of the neck, filled with heparinized saline, and capped until needed for an experiment. A small temperature telemetry transmitter (Mini Mitter, Sunriver, OR) was also placed into the abdominal cavity of the rat. For blood-gas measurements, the rat was placed in the plethysmographic chamber with the catheter connecting via a swivel to a heparinized syringe. Blood gases were measured during resting E and during the hypoxia stimulation (12% O2). Blood was drawn during the last minute of the first and last episodes (n = 1 for protocol 1 and n = 2 for protocol 2) of hypoxia and analyzed for the pH value and the partial pressure of O2 (PaO2) and CO2 (PaCO2) in arterial blood (ABL 700; Radiometer, Copenhagen, Denmark) with correction for the rat's body temperature from telemetry. These values were averaged to briefly assess the hypoxemic and hypocapnic levels in these protocols compared with other LTF studies.
Time-Control Rats
In another separate group of 8 rats, ventilatory LTF, elicited by 5 (n = 4) or 10 episodes (n = 4) of 12% O2, was measured four times on the same rats, before (n = 4) and at 8 h (n = 4), 3 days (n = 2), and 7 days (n = 4) after exposure to normoxia. These rats were exposed to the same noise as the CIH-treated rats but were exposed to only air (normoxia). These measurements were all made at the same time of day as for the CIH-treated rats.
Data Analysis
E, fR, VT, TI, and TE were measured in rats that were observed to be awake and in a quiet state. Data recorded when the rats were not both quiet and awake (e.g., moving or asleep) were rejected from the analysis. This rejection was done blindly, i.e., E was unknown when it was rejected for movement artifact. Furthermore, an additional algorithm is included in the computer software breath-by-breath analysis that allows for further rejection of artifactual breaths.
To facilitate analysis, LTF is also numerically expressed as a magnitude and duration as previously described (28). Briefly, the LTF magnitude was determined by the average of the first three E values recorded at 15, 30, and 45 min posthypoxia and expressed as a percentage above the baseline value. The magnitude of LTF was thus calculated by the equation %[(E15 + E30 + E45)/3 - baseline]/baseline. The duration of LTF was defined as the last posthypoxia time point at which E was significantly higher than baseline.
The LTF duration for each group and the between-group differences in baseline and the individual posthypoxia E (absolute values) were determined by using a two-way analysis of variance (ANOVA) with repeated measures (Sigma-Stat version 2,0, Jandel, San Rafael, CA), followed by the Student-Newman-Keuls post hoc tests. Only baseline and posthypoxia data were included in this analysis (data recorded during AIH not included). The differences before and after AIH or CIH in TI, TE, TI/TT [ratio of TI to (TI + TE)], VT, VT/TI (inspiratory drive), and fR (absolute values) were also analyzed by two-way ANOVA. All other differences were determined by a one-way ANOVA, including the between-group differences in ventilatory, VT, and fR LTF (percentage values calculated by the 3-value-average method) and the between- and within-group differences in HVR and metabolic rate values. P < 0.05 was considered significant. All values are expressed as means ± SE.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Baseline
The recording traces representing the breathing pattern under different conditions are shown in Fig. 1. In the baseline condition, E, CO2, and E normalized to metabolic rate (E/CO2) were all unchanged after CIH treatment (all P > 0.56; Table 1), as were TI, VT, fR, and inspiratory drive (VT/TI) (Table 2). However, there was a slight but significant increase in TE and O2 8 h after CIH treatment (Tables 1 and 2). The average HVR was also unchanged after CIH (P = 0.51; Table 1). These data indicated that the resting E, metabolic rate, and HVR (to 12% O2) were unchanged after CIH treatment.
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Protocol 1
Five episodes of 12% O2 were an originally ineffective protocol because it did not elicit ventilatory LTF in awake rats before CIH. However, at 8 h after CIH, the same protocol elicited LTF with a magnitude of 23.5 ± 1.4% (calculated by the 3-value-average method) and a duration of 75 min (Fig. 2). This CIH-induced enhancing effect was still partially present 3 days after CIH as protocol 1 elicited LTF although of smaller magnitude (11.4 ± 2.2%, P < 0.05) and shorter duration (45 min). However, this CIH effect had disappeared 7 days after CIH as protocol 1 failed to induce LTF (Fig. 2). These statements were also supported by the absolute-value analysis (2-way ANOVA). There was a significant interaction between group and time factors in posthypoxia E [F(18, 104) = 10.2; P < 10-6], and the between-group differences in those individual posthypoxia E were also consistent with the above percentage results (Fig. 2).
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LTF of fR was increased 8 h after CIH (Fig. 3B) because of the shortened TE and TI (Table 2). LTF of VT was not significantly different from the pre-CIH value although appeared to be higher (Fig. 3A); however, VT/TI was increased after CIH (Table 2). At 3 days post-CIH, both fR and VT LTF appeared to remain slightly higher than baseline, but these changes were not significant. Both VT and fR LTF had returned to pre-CIH values at 7 days post-CIH (Fig. 3). These data indicate that CIH enhances LTF by converting an ineffective protocol to an effective one and that this post-CIH LTF results mainly from fR LTF (owing to TI and TE reduction). These data also suggest that the CIH effect on LTF can persist for at least 3 days but less than 7 days.
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Protocol 2
Ten episodes of 12% O2 elicited LTF with a magnitude of 17.7 ± 1.1% and a duration of 45 min before CIH. About 8 h after CIH, the same protocol elicited an enhanced LTF with a magnitude of 29.1 ± 1.5% and duration of 75 min (Fig. 4). The CIH effect on LTF magnitude seemed to disappear by 3 days (20.4 ± 2.1%; P = 0.277), but LTF duration was still longer (60 min) than its pre-CIH value (Fig. 4). By 7 days the CIH effect on LTF had disappeared as both the magnitude and duration of LTF returned to the pre-CIH values. In the absolute value analysis, there was a significant interaction between group and time factors in posthypoxia E [F(18, 107) = 7.7; P < 10-6], and the differences in the individual posthypoxia E were also consistent with the percentage results (Fig. 4).
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The pre-CIH ventilatory LTF resulted mainly from fR LTF (owing to TI reduction, Table 2) with little VT LTF (Fig. 5), but VT/TI was increased (P < 0.05; Table 2). The CIH-induced enhancement of LTF at 8 h post-CIH was mainly due to an increase in VT LTF (P < 0.05) with no significant increase in fR LTF (P = 0.42; Fig. 5B). Posthypoxia TI and TE were shortened, and VT, VT/TI, and fR were increased from baseline (Table 2). At 3 days post-CIH, both VT and fR LTF returned to pre-CIH values although VT LTF appeared to remain slightly higher (insignificant, P = 0.11). By 7 days there was no difference left in either VT or fR LTF (Fig. 5). These data indicate that CIH augments LTF magnitude and prolongs LTF duration and suggest that CIH enhances the ventilatory LTF, elicited by an originally effective protocol, mainly by increasing VT LTF and VT/TI.
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Time Controls
There was no difference between the four measurements of either protocol in baseline CO2 or HVR (data not shown). Resting and post-AIH E, which were normalized to the body weight, were also similar among the measurements (Fig. 6). These results suggest that there was no confounding carryover effect on these parameters in those repeated measurements.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Methodological Consideration
The use of barometric plethysmography to measure E and metabolic rate in awake rats provided a more natural and physiological way to investigate this CIH effect, as possible confounding issues related to anesthesia, surgery, and restraint could be eliminated and the metabolism could also be taken into consideration. It is known that E can be affected by changes in blood gases (PaO2 and PaCO2), metabolic rate, body temperature, and/or respiratory dead space. However, in our previous study using similar protocols (28), body temperature was unchanged by 5-min hypoxic episodes. The CO2 production, PaO2, and respiratory dead space also appeared to return to baseline values at 15 min posthypoxia, suggesting that the intermittent hypoxia protocol-induced changes in these parameters have little carryover effect on the posthypoxia E values that determine LTF. These rats, however, still appeared to be slightly hypocapnic (3 Torr lower in PaCO2), owing likely to ventilatory LTF (28).
The present study was conducted according to a complete within-subject experimental design, i.e., the measurement protocol was repeated four times on the same rats. This experimental design plus the strict rule (i.e., measurement only during quiet wakefulness) improved consistency of our result by reducing data variability. There is no confounding carryover effect in this design because no difference in either ventilatory or metabolic parameters was found among these measurements in the time-control experiments. This notion is also supported by the unaltered, resting E and other baseline values at different times after CIH treatment (Table 1). In addition, it has been shown that 1 day or even several hours after the first measurement of ventilatory LTF had no carryover effect on the second one (30, 40).
In our previous study, both hypoxic severity and episode number in stimulus protocols were shown to affect the elicitation, maintenance, and size of ventilatory LTF in awake rats (28). Therefore two stimulus protocols, one ineffective and another effective in inducing LTF, were used in the present study to more broadly examine the CIH effect on LTF. Using a subthreshold protocol (5 episodes of 12% O2) helped to reveal the CIH effect on the stimulus intensity threshold for eliciting LTF and to demonstrate the persistence period of the CIH effect on LTF, which could be easily masked by normal LTF as was the case when using an originally effective protocol.
Effect of CIH
In the present study, CIH did not change resting E. If the resting E had significantly changed after CIH, it could have complicated the data analysis, because HVR and LTF are normalized to this resting E. In the present study, the HVR (to 12% O2) was also unchanged after CIH. This observation is not consistent with the study using anesthetized rats (20), in which the phrenic response to hypoxia was greatly enhanced after CIH, as well as other awake studies in which HVR was enhanced after other forms of CIH in human subjects (16, 46). The unchanged HVR in the present study might be due to a CIH effect on the arterial blood-gas responses to poikilocapnic hypoxia. In separate rats (n = 3), blood gases were measured before and 8 h after CIH. The same 12% O2 induced less severe hypoxemia (Control: 38.2 ± 0.8 vs. CIH: 43.6 ± 1.8 Torr) and more severe hypocapnia (30.5 ± 0.1 vs. 26.0 ± 2.9 Torr) after CIH, which presumably produced a relatively weaker stimulus to the peripheral chemoreceptors, thus compromising the possible CIH-induced enhancement in the peripheral chemoreflex.
In the anesthetized study (20), because of the lower CO2-apneic threshold, the baseline PaCO2 level was also set 6 Torr lower in CIH-treated vs. control rats. Eldridge et al. (8) have shown that the input-output relationship of the respiratory central neural circuits is not linear, e.g., the phrenic response to a constant hypoxic stimulus was progressively reduced in magnitude as the prestimulus level of respiratory activity was increased. Therefore, the lower baseline setting in the anesthetized study might not only reduce the baseline per se (the denominator of the normalization) but also increase the phrenic response to a given hypoxic stimulation, both of which would enlarge the assessment of the hypoxic phrenic response normalized to baseline value. In support of this argument, the ratio of baseline phrenic activity to the approximately maximal phrenic response to hypercapnia was significantly lower in those CIH-treated rats (untreated control: 42.4 ± 2.0%, n = 22; CIH-treated: 26.0 ± 1.6%, n = 18; P < 0.05; Ling L, Fuller DD, Bach KB, Kinkead R, Olson EB, and Mitchell GS, unpublished data). Therefore, we now believe that the CIH-induced enhancement of the hypoxic respiratory response was overestimated in the study by Ling et al. (20), as was the enhancement of phrenic LTF after CIH (doubled in magnitude from 40 to 80% at the 60-min posthypoxia time point).
There is a weak but significant correlation between hypoxic phrenic response and phrenic LTF magnitude in anesthetized rats (13), suggesting that the size of the hypoxic response may somehow determine LTF magnitude. However, in the present study, HVR was not augmented whereas LTF was enhanced. In a separate study (29) using another effective LTF stimulus protocol (5 episodes of 10% O2), although ventilatory LTF was similarly enhanced by CIH (from 18.3 ± 0.5% magnitude with 45-min duration in control to 28.0 ± 0.9% magnitude with 75-min duration after CIH), HVR to 10% O2 was even significantly decreased (151 ± 2% above baseline vs. 132 ± 8%). Therefore, these data suggest that CIH does not enhance ventilatory LTF through increasing hypoxic responsiveness.
The persistence period of the CIH effect on ventilatory LTF lasted for at least 3 days but was less than 7 days. However, this 3-day persistence was only seen when using protocol 1. We believe that in experiments using protocol 2, the CIH effect at 3 days after CIH might be masked because protocol 2 initially elicits LTF without CIH and its magnitude appears to be greater than the one elicited by protocol 1 at 3 days after CIH. These data suggest that the CIH-induced enhancing effects on LTF are not simply added on the original LTF.
It is unclear why CIH induced different pattern of LTF enhancement (VT vs. fR) when using different AIH protocols. However, this difference may somehow relate to the different post-AIH fR (see Table 2). In protocol 1 cases, the post-AIH fR was 86 (breaths/min), little different from its baseline value. In protocol 2 cases, however, the post-AIH fR was almost 100 (breaths/min), a rather higher fR in resting condition. We speculate that it is this higher fR that makes the respiratory control system recruit other means (e.g., VT) to increase E when ventilatory LTF is enhanced after CIH.
Intermittent Hypoxia
Compared to sustained hypoxia, the effects of intermittent hypoxia (especially CIH) on respiration have been less well studied (cf. Refs. 4, 5). There are also fundamental differences between sustained and intermittent hypoxia in their influence on hypoxic ventilatory control. For example, AIH evokes LTF (2, 3, 6, 28, 40, 47), but sustained hypoxia does not, even with longer exposures (3, 7, 10). These results suggest that intermittent hypoxia affects the hypoxic ventilatory control system in a different way than sustained hypoxia.
Many forms of intermittent hypoxia are known to lead to pathological consequences, e.g., right ventricular hypertrophy (25, 38), pulmonary hypertension (26, 38), and restriction of fetal growth (45). CIH has been implicated in systemic hypertension (11), sudden infant death syndrome (42), and the pathological consequences of obstructive sleep apnea (OSA; Ref. 44). Paradoxically, some forms of intermittent hypoxia are known to provide protection from cardiac arrhythmias (34), lethal hypoxia (22), and ischemia-induced injury (48). Some believe that adaptation to one stress builds resistance to another (33) and that adaptation to stress enhances the expression of stress protein and antioxidant systems (32). However, the basic mechanisms underlying both beneficial and pathological effects of intermittent hypoxia are not well understood (cf. Ref. 39), particularly in respect to the neural mechanisms involved.
We believe that the paradoxical consequences might result from different protocols. For example, the intermittent hypoxia protocols with pathological effects usually employ rapid and severe hypoxia, whereas the intermittent hypoxia protocols with beneficial effects usually utilize moderate hypoxia with longer duration. Thus the pathological effects of intermittent hypoxia are probably related to the hypoxic severity and the speed of reaching hypoxic nadir and reoxygenation. The AIH and CIH protocols, used in the present study and the anesthetized one (20), seem to approximate those used in the studies of beneficial effects. Thus these protocols were not intended to mimic the episodes of hypoxic apnea that often occurred in OSA patients but to create an effective tool (induction of system neural plasticity by physiological stimulation) to explore the neural networks of the hypoxic ventilatory control system. The CIH treatment was also purposely conducted at night during rats' normal awake, active period, thereby avoiding sleep deprivation or fragmentation.
Potential Mechanisms
The CIH effect on LTF is unlikely mediated through the changes in hormones (e.g., epinephrine and norepinephrine) or blood gases and pH, as most data were collected 8 h or even 3 days after CIH, and this CIH effect can be completely blocked by serotonergic receptor antagonism. Methysergide (a broad-spectrum serotonin receptor antagonist) totally abolished both phrenic LTF and the CIH-enhanced phrenic LTF in anesthetized rats, suggesting that both LTF per se and the CIH-induced enhancement of LTF require serotonergic mechanisms (20). On the other hand, although ketanserin (a specific 5-HT2 receptor antagonist) abolished phrenic LTF, it only partially blocked the CIH-enhanced phrenic LTF, suggesting that the CIH-induced enhancement of LTF is mediated through non- 5-HT2 serotonin mechanisms (20). Thus, although LTF per se and the CIH effect on LTF are similar in some aspects, they are different in at least two aspects: 1) the role of 5-HT2 receptors, and 2) their persistence period (minutes or hours vs. days).
The hypothetical mechanism of LTF has been proposed and refined many times (9, 13, 36). For phrenic LTF, briefly, carotid body chemoafferents, activated by intermittent hypoxia or CSN stimulation, project to both the raphe nuclei and the integrative centers responsible for respiratory rhythm generation and burst pattern formation. These medullary nuclei then activate each other as well as phrenic motoneurons. Released serotonin from the raphe serotonergic neurons activates 5-HT2 receptors on the phrenic motoneurons, which initiates a series of intracellular signaling events, leading to phrenic LTF. These concepts are supported by many studies (cf. Refs. 9, 13, 36).
It is unclear how CIH enhances LTF. However, on the basis of our results and information available, we speculate that CIH repeatedly activates the neural networks, which leads to an activity-dependent upregulation of serotonin receptors on the phrenic motoneurons. These newly synthesized serotonin receptors (mainly of non-5-HT2 subtype) increase the overall efficacy of the serotonergic synaptic transmission, which then augments the intracellular signaling events, thus enhancing subsequent LTF when it is evoked. There is supportive evidence for these speculations. It has been reported that serotonin receptors can be upregulated by either serotonin hyperinnervation or reuptake blockade (18) and downregulated by chronic serotonin receptor antagonism (19). As for location(s), there has been evidence suggesting that this CIH effect is primarily a central mechanism (20). However, this conclusion might also be overestimated (or even mistaken) because of the same baseline setting (see Effect of CIH).
A recent study by Peng and Prabhakar on anesthetized rats (41), using hypoxic protocols that mimic hypoxic episodes of OSA patients, showed that AIH elicited phrenic LTF and prior conditioning with CIH also enhanced this LTF. In addition, this CIH effect on LTF was eliminated by systemic injection of a potent scavenger of O2-· radicals before CIH, suggesting that reactive O2 species (ROS), especially the O2-· radicals, play a role in this CIH effect (41). There was also evidence suggesting that this CIH enhanced (or revealed) the LTF of carotid chemoafferent activity (43). Collectively, these data suggest that the CIH effect on LTF may require ROS as well as serotonergic mechanisms and that the carotid body may be an important location for the CIH effect. It is possible that the reduction of the CIH effect on ventilatory LTF, observed in the present study at 3 days after CIH, results from a decline of the ROS and/or the non-5-HT2 serotonin receptors. However, caution should be used for such a generalization because the CIH effects induced by different protocols might use different mechanisms.
Significance
Plasticity of neural pathways and networks is of broad scientific interest and impacts on our understanding of learning, memory, and the behavior of complex motor systems. Although progress has been made in recent years, the plasticity in mammalian respiratory motor control remains poorly understood. Our data indicate that repeated (physiological) activation of the hypoxic ventilatory control system, by exposure to CIH, induces long-lasting forms of plasticity in this system and suggest that fully developed, adult mammals can still exhibit substantial plasticity in the respiratory control mechanisms as a result of certain experiences.
Although the CIH protocol in the present study was not explicitly designed to simulate the nocturnal intermittent hypoxia that often occurs in OSA patients, our results may still have some clinical implication. LTF has been expressed in a number of animal species but not in normal awake humans (15, 24). However, LTF was induced in snorers with inspiratory flow limitation during non-rapid eye movement sleep (1) and OSA patients during wakefulness (31). This could be because these people had experienced some form of CIH, thus reducing the stimulus intensity threshold for eliciting LTF. In addition, because LTF is thought to possibly stabilize breathing and upper airway function, we believe that certain forms of CIH might contribute to improving upper airway patency by enhancing LTF mechanisms. These arguments, however, are speculative and await direct, experimental verification.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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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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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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T. E. Dick, Y.-H. Hsieh, N. Wang, and N. Prabhakar Acute intermittent hypoxia increases both phrenic and sympathetic nerve activities in the rat Exp Physiol, January 1, 2007; 92(1): 87 - 97. [Abstract] [Full Text] [PDF]
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V. A. Braga, R. N. Soriano, and B. H. Machado Sympathoexcitatory response to peripheral chemoreflex activation is enhanced in juvenile rats exposed to chronic intermittent hypoxia Exp Physiol, November 1, 2006; 91(6): 1025 - 1031. [Abstract] [Full Text] [PDF]
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D. P. Harris, A. Balasubramaniam, M. S. Badr, and J. H. Mateika Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1111 - R1119. [Abstract] [Full Text] [PDF]
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M. McGuire, Y. Zhang, D. P. White, and L. Ling Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats J. Physiol., September 1, 2005; 567(2): 599 - 611. [Abstract] [Full Text] [PDF]
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E. Gozal, Z. A. Shah, J.-M. Pequignot, J. Pequignot, L. R. Sachleben, M. F. Czyzyk-Krzeska, R. C. Li, S.-Z. Guo, and D. Gozal Tyrosine hydroxylase expression and activity in the rat brain: differential regulation after long-term intermittent or sustained hypoxia J Appl Physiol, August 1, 2005; 99(2): 642 - 649. [Abstract] [Full Text] [PDF]
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M. McGuire and L. Ling Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats J Appl Physiol, April 1, 2005; 98(4): 1195 - 1201. [Abstract] [Full Text] [PDF]
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S. Rey, R. Del Rio, J. Alcayaga, and R. Iturriaga Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia J. Physiol., October 15, 2004; 560(2): 577 - 586. [Abstract] [Full Text] [PDF]
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S. R. Reeves and D. Gozal Platelet-activating factor receptor modulates respiratory adaptation to long-term intermittent hypoxia in mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R369 - R374. [Abstract] [Full Text] [PDF]
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R. W. Bavis, E. B. Olson Jr, E. H. Vidruk, D. D. Fuller, and G. S. Mitchell Developmental plasticity of the hypoxic ventilatory response in rats induced by neonatal hypoxia J. Physiol., June 1, 2004; 557(2): 645 - 660. [Abstract] [Full Text] [PDF]
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Y.-J. Peng and N. R. Prabhakar Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity J Appl Physiol, March 1, 2004; 96(3): 1236 - 1242. [Abstract] [Full Text] [PDF]
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M. McGuire, Y. Zhang, D. P. White, and L. Ling Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R334 - R341. [Abstract] [Full Text] [PDF]
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significant difference from 8-h posttreatment group (P < 0.05).
