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J Appl Physiol 90: 1729-1735, 2001;
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Vol. 90, Issue 5, 1729-1735, May 2001

Stress-induced attenuation of the hypercapnic ventilatory response in awake rats

Richard Kinkead, Lydie Dupenloup, Nadine Valois, and Roumiana Gulemetova

Department of Pediatrics, Laval University, Hôpital St-François d'Assise, Unité de Recherche de Périnatalogie, Quebec City, Quebec, Canada G1L 3L5


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

To test the hypothesis that stress alters the performance of the respiratory control system, we compared the acute (20 min) responses to moderate hypoxia and hypercapnia of rats previously subjected to immobilization stress (90 min/day) with responses of control animals. Ventilatory measurements were performed on awake rats using whole body plethysmography. Under baseline conditions, there were no differences in minute ventilation between stressed and unstressed groups. Rats previously exposed to immobilization stress had a 45% lower ventilatory response to hypercapnia (inspiratory CO2 fraction = 0.05) than controls. In contrast, stress exposure had no statistically significant effect on the ventilatory response to hypoxia (inspiratory O2 fraction = 0.12). Stress-induced attenuation of the hypercapnic response was associated with reduced tidal volume and inspiratory flow increases; the frequency and timing components of the response were not different between groups. We conclude that previous exposure to a stressful condition that does not constitute a direct challenge to respiratory homeostasis can elicit persistent (>= 24 h) functional plasticity in the ventilatory control system.

restraint stress; hypercapnia; control of breathing; plasticity; hypoventilation


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

REPEATED EXPOSURE TO VENTILATORY stimuli elicits functional plasticity within the respiratory control system. For instance, repeated hypoxic or electrical activation of peripheral chemoafferent neurons evokes a persistent increase in ventilatory activity that remains for hours after the final stimulation episode (long-term facilitation) (2, 14, 30, 38). In contrast, intermittent exposure to severe hypercapnia [inspiratory CO2 fraction (FICO2) = 0.10] results in a long-lasting, alpha 2-adrenoceptor-dependent depression of respiratory motor output (3). On a different time scale, exposing adult rats to intermittent hypoxia for 1 wk increases phrenic burst frequency and amplitude responses to electrical stimulation of the carotid sinus nerve (25). Although much remains unknown about neural mechanisms involved in respiratory plasticity, the present working hypothesis states that repeated hypoxic or hypercapnic stimulation of chemosensory neurons elicits release of modulatory neurotransmitters that facilitate (or attenuate) the relationship between descending respiratory drive and respiratory motor output (28). Consistent with this hypothesis, increasing the capacity for serotonergic modulation has been correlated with enhancement of long-term facilitation (22).

Much like repeated exposure to systemic stresses (i.e., hypoxia and hypercapnia), acute psychological stress elicits important humoral and neural responses (1). The latter includes release of several neuromodulators (including monoamines such as serotonin and norepinephrine) known to modulate the activity of respiratory neurons (5, 6, 19). With time, repeated stress exposure elicits important neural plasticity that is part of a series of compensatory mechanisms aimed at attenuating the deleterious effects of stress (29, 41). These acute and chronic responses to stress take place in several central nervous system regions, including brain stem neurons contributing to respiratory control (7, 27).

Immobilization is a processive (i.e., nonsystemic) stress that activates complex neuroendocrine responses but, unlike hypoxia or hypercapnia, does not constitute a direct challenge to respiratory homeostasis. Immobilization is commonly used, because it is a relatively mild, nonnociceptive stressor; its effects are constant (repeatable) and well characterized (15, 35). Immobilization stress increases activity of neurons having significant modulatory influences on respiratory neurons such as locus ceruleus and A1/C1 catecholaminergic neurons (24). Moreover, exposure to a single restraint stress episode increases Fos labeling in brain stem regions involved in respiratory control, such as the ventrolateral medulla (7, 27). Because increased Fos expression can couple short-term events with long-term changes in gene expression (31), stress may also exert long-lasting effects on respiratory neurons by altering their membrane properties or changing the strength of neuromodulatory influences. Although these data suggest that exposure to a stressful situation that is not directly relevant to respiration could modify the performance of the respiratory control system, the functional consequences of processive stress exposure on the respiratory control system have not been addressed. To test the hypothesis that immobilization stress elicits plasticity in the respiratory control system, we compared the hypoxic and hypercapnic ventilatory responses of awake, unrestrained rats previously subjected to daily psychological stress sessions (immobilization stress for 90 min/day) with those of routinely handled animals.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Experiments were performed on 70 adult male Sprague-Dawley rats (357 ± 8 g; Charles River Canada, St-Constant, PQ, Canada). Rats were supplied with food and water ad libitum and maintained in standard laboratory conditions (20°C, 12:12-h dark-light cycle: lights on at 0600 and off at 1800). To address the effects of processive (i.e., psychological, nonsystemic) stress on ventilatory control, the study involved two series of ventilatory measurements (hypoxia and hypercapnia) that were performed 24 h after the end of the immobilization stress protocol. In each series, three groups of animals were studied, and each group received a different number of daily stress sessions before ventilatory measurements. All experiments were performed according to the guidelines of the Canadian Council on Animal Care. The institutional animal care committee approved the specific protocols.

Experimental groups and protocol summary. Series I tested the effects of immobilization stress on the hypoxic ventilatory response [inspiratory O2 fraction (FIO2) = 0.12]; series II addressed the effects of immobilization stress on the ventilatory response to hypercapnia (FICO2 = 0.05). Each series involved three groups: nonstressed control rats (n = 20 and 16 for series I and II, respectively) and rats exposed to one (n = 5 for both series I and II) or two (n = 11 and 13 for series I and II, respectively) daily immobilization stress sessions.

Ventilatory responses to hypoxia or hypercapnia were measured by whole body plethysmography 24 h after the last stress session. In some animals in each group, a chronic indwelling arterial catheter was placed for analysis of arterial blood gases. Ventilatory responses of rats in which blood samples were taken were not different from those of nonsampled animals (P = 0.53 and 0.57 for series I and II, respectively).

Immobilization stress protocol. An immobilization stress session consisted of placing the rat in a Broome rodent restrainer for 90 min. For each series, one group of rats was exposed to a single stress session and a second group was subjected to the stress protocol on 2 consecutive days. The stress protocol was always performed between 0900 and 1200. For each series (hypoxic and hypercapnic), the corresponding control group consisted of rats that were not subjected to the stress protocol.

Surgical procedure. A catheter was placed in the femoral artery of rats for blood sampling and measurement of arterial blood gases and pH. Arterial catheters were placed under isoflurane anesthesia (2-2.5% in O2). Once in position, the catheter was routed under the skin to the back of the neck and filled with heparinized saline (10 U/ml). Postsurgical care consisted of two subcutaneous injections of an anti-inflammatory drug (ketoprofen, 2 mg/kg): one immediately after the surgery and another 24 h later. The second catheter was flushed once daily with heparinized saline to ensure patency. Rats recovered for >= 48 h before ventilatory measurements were made.

Measurements of ventilation and arterial blood gases. Ventilation of tethered (with catheters only), but otherwise unrestrained, unanesthetized rats was measured using a whole body, flow-through plethysmograph (model PLY3223, Buxco Electronics, Sharon, CT). The system was similar to that described by Hamelmann et al. (16) and consisted of a 4.5-liter Plexiglas experimental chamber equipped with two pneumotachographs with a defined resistance. Differential pressure between the experimental and reference chambers was measured with a differential pressure transducer (SenSym) with a fast response time (500 µs). The pressure signal was amplified and then integrated by data analysis software (Buxco Biosystem XA). The system was calibrated by injecting a known volume (1 ml) into the chamber with a glass syringe. The barometric pressure and rat body weight were recorded daily, and the chamber temperature and humidity and core temperature of the animal were measured at the beginning and end of each experimental period. These data were used to express tidal volume (VT) in milliliters (BTPS) per 100 g. Fresh air or gas mixtures were delivered to the experimental chamber at a constant rate with a bias flow regulator (model PLY1020, Buxco Electronics). The gas mixture flowing out of the chamber was analyzed with a flow-through capnograph (Novametrix, Wallingford, CT) for subsequent calculation of CO2 production (VCO2) with an open system according to the method and equations described by Mortola and Dotta (32). CO2 measurements from the outflowing gas mixture also ensured that CO2 levels within the chamber always remained below 0.5%. Typical airflow ranged between 2.0 and 2.5 l/min.

After rectal (core) temperature was recorded, the rat was placed in the box with room air flowing through. When necessary, the arterial catheter was connected to the swivel for blood sampling. The animal would typically explore the surroundings, groom itself, and then settle down. Baseline measurements were made when the animal was quiet but awake and breathing room air. A first arterial blood sample of 100 µl was taken at that time. Arterial blood samples were obtained by slowly drawing enough blood (~0.3 ml) to ensure that the blood within the catheter was not diluted with saline. The catheter was then disconnected from its extension near the experimental chamber and placed into a small heparinized glass capillary that fitted tightly around the catheter, thus avoiding exposure of the blood to room air. Blood would then rapidly flow within the capillary (due to blood pressure and/or gravity pull), and the sample was analyzed immediately. Then a gas mixture of 12% O2 or 5% CO2 in air was delivered to the chamber for 20 min, and a second arterial blood sample was taken before the recording chamber was opened for a final body temperature measurement. Blood samples were analyzed for arterial PO2 (PaO2), PCO2 (PaCO2), and pH (AVL, model 995). In each series, animals were exposed to only one respiratory stimulus. All measurements were performed between 1000 and 1500.

Data analysis. Baseline measurements of ventilatory variables were obtained by averaging 10 min of stable recording, whereas a 5-min average was taken for each variable at the end of the hypoxic or hypercapnic exposure. The results were analyzed statistically using a two-way ANOVA (Statview 5.0, SAS Institute, Cary, NC) followed by a post hoc Fisher's protected least significant difference test (P < 0.05). A repeated-measure design was used when appropriate.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Immobilization stress and "resting" ventilation. Baseline ventilatory measurements obtained in both series of experiments were comparable to those reported in other studies using Sprague-Dawley rats under similar experimental conditions (8, 12, 13, 34, 36). Exposure to one or two stress sessions did not have any statistically significant effect on any of the ventilatory variables measured under normoxic normocapnic conditions (Tables 1 and 2; Figs. 1 and 2). However, both groups of stressed rats had slightly greater VCO2 and PaCO2 values than control animals (Tables 1 and 2).

                              
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  		Table 1.   Effects of stress on ventilatory variables, arterial blood gases, and CO2 production under normoxic (baseline) and hypoxic conditions in awake rats: Series I


                              
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  		Table 2.   Effects of stress on ventilatory variables, arterial blood gases, and CO2 production under normoxic (baseline) and hypercapnic conditions in awake rats: series II



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  		Fig. 1.   Acute hypoxic ventilatory response in unstressed rats (controls, n = 20) or rats exposed to 1 (n = 5) or 2 (n = 11) immobilization stress sessions (90 min/day). Breathing frequency, tidal volume (VT), minute ventilation, and mean inspiratory flow (VT/TI) were measured 24 h after the last stress session under baseline conditions (normoxic normocapnia) or after 20 min of exposure to hypoxia (inspired O2 fraction = 0.12). Previous exposure to immobilization stress did not affect the ventilatory response to hypoxia in awake rats. Values are means ± SE. VT is expressed in ml BTPS /100 g; VT/TI is expressed in ml BTPS/s. *Statistically different from baseline (P < 0.05).



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  		Fig. 2.   Acute ventilatory response to hypercapnia in unstressed rats (controls, n = 16) or rats exposed to 1 (n = 5) or 2 (n = 13) immobilization stress sessions (90 min/day). Breathing frequency, VT, minute ventilation, and VT/TI were measured 24 h after the last stress session under baseline conditions (normoxic normocapnia) or after 20 min of exposure to moderate hypercapnia (inspired CO2 fraction = 0.05). Previous exposure to a single immobilization stress session is sufficient to attenuate the ventilatory response to hypercapnia in awake rats. Values are means ± SE. VT is expressed in ml BTPS/100 g; VT/TI is expressed in ml BTPS/s. *Statistically different from baseline; dagger statistically different from corresponding control (P < 0.05).

Immobilization stress and hypoxic ventilatory response. In this series, isocapnia was not maintained during hypoxia; yet, PaO2 and PaCO2 were reduced equally in all three groups. Ventilatory measurements obtained at the end of the hypoxic stimulus revealed no difference between stressed and control rats (Fig. 1, Table 1). Similarly, hypoxic values for the ratio of VT to inspiratory time (Vt/TI), an index of inspiratory effort, were not different between stressed and unstressed rats (Fig. 1D). Mean VCO2 was unaffected during the first 20 min of hypoxia in all groups (Table 1), in agreement with previous reports (26).

To further analyze the effects of stress on the hypoxic response, selected ventilatory variables were normalized and expressed as a percent change from baseline values. Although this additional analysis suggests that exposure to two stress sessions may attenuate the hypoxic increase in minute ventilation, this observation was not statistically significant (Fig. 3).


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  		Fig. 3.   Normalized ventilatory responses to hypoxia (fraction of inspired O2 = 0.12, series I, A) and hypercapnia (fraction of inspired CO2 = 0.05, series II, B) in stressed and control rats. Percent changes from normoxic baseline values in minute ventilation (VI), breathing frequency, VT, and VT/TI were obtained 20 min after the onset of the ventilatory stimulus in control rats and rats subjected to 1 or 2 immobilization stress sessions (90 min/day). Exposure to stress 24 h before ventilatory measurements attenuates the ventilatory response to hypercapnia but not hypoxia. This stress-induced attenuation of the hypercapnic response is caused mainly by a reduced inspiratory effort. Statistically different from control: *P < 0.05 and Dagger P < 0.10.

Immobilization stress and hypercapnic ventilatory response. Exposure to moderate hypercapnia had a significant effect on all variables reported in Table 2. Specifically, inspiratory and expiratory duration were shortened, PaO2 and PaCO2 increased, and arterial pH and body temperature decreased. Changes in PaO2 and PaCO2 were not different between experimental groups. These responses to hypercapnia were not affected by previous stress exposure, as indicated by the lack of statistical interaction between the two factors. VCO2 was reduced (Table 2), in accordance with the study of Ling et al. (26). Expressing hypercapnia-induced changes in VCO2 as a percent change from baseline revealed no difference between stressed and unstressed rats (P = 0.345; data not shown).

Exposure to a single immobilization stress session was sufficient to attenuate the hypercapnic ventilatory response. This effect of immobilization stress was also detected in rats exposed to two stress sessions (Fig. 2). Reduced responsiveness to hypercapnic stimulation was not related to the frequency component of the response; neither the breathing frequency nor the timing of the breathing cycle was affected by immobilization stress (Fig. 2A, Table 2). In contrast, the increase in VT during hypercapnia was less in both groups of rats exposed to immobilization stress (Fig. 2B) owing to a lower increase in inspiratory effort as indicated by VT/TI calculations (Fig. 2D). Statistical analysis revealed significant interactions between stress and hypercapnia on minute ventilation, VT, and VT/TI, indicating that stress exposure significantly reduced the ability to respond to hypercapnia (P = 0.032, 0.013, and 0.030, respectively).

Again, expressing the hypercapnic ventilatory response in terms of percent change from baseline values confirmed that stress exposure was associated with a reduced responsiveness to hypercapnia. Figure 3B shows that the increase in minute ventilation during hypercapnia was less in both groups of rats subjected to our immobilization stress protocol, owing mainly to a reduced VT response and VT/TI. Immobilization stress did not affect the frequency component of the response (P = 0.641).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Collectively, our results indicate that exposure to a single session of processive (i.e., nonsystemic) stress is sufficient to alter the responsiveness to moderate hypercapnia in awake rats, even though immobilization stress does not constitute a direct challenge to respiratory homeostasis. This manifestation of respiratory plasticity, which persisted for >= 24 h after the last stress session ended, may be unique to the neural circuits involved in the ventilatory response to hypercapnia, because immobilization stress did not affect the hypoxic ventilatory response. Our results are consistent with our working hypothesis that exposure to processive stress can elicit persistent functional plasticity of neural circuits involved in ventilatory control.

Stress and ventilatory response to hypercapnia. In both series of experiments, VCO2 and PaCO2 values were elevated in stressed rats vs. control animals. Although the increase in VCO2 is in accordance with other reports suggesting that restraint stress increases metabolism (23, 33), the lack of significant differences in resting minute ventilation between groups is consistent with a potential reduction in the resting hypercapnic ventilatory drive in stressed rats. These results are in agreement with plethysmographic measurements showing that previous exposure to a single immobilization stress session is sufficient to attenuate the ventilatory response to moderate hypercapnia in awake rats. Previous stress exposure did not affect the timing and frequency component of the hypercapnic response but reduced the magnitude by which VT/TI and VT increased during hypercapnia, thus indicating that the stress-induced attenuation of the hypercapnic ventilatory response was related to a reduction in inspiratory effort.

Isom and Elshowihy (20) reported that rats exposed to inescapable foot shock displayed an increase in respiratory rate, VT, and minute ventilation and that systemic pretreatment with the opioid receptor antagonist naloxone hydrochloride potentiated this response. Their study also showed that the hypercapnic ventilatory response was attenuated after chronic exposure (11 daily sessions) to this stress paradigm. On the basis of these results, these authors concluded that endogenous opioids prevent excessive stimulation of respiration by stress. Several important differences in experimental protocol prevent us from extending this conclusion to our results. For instance, Isom and Elshowihy measured ventilatory responses immediately after stress exposure, whereas our measurements were performed 24 h after the last stress session. Moreover, unlike immobilization stress, foot shock is a nociceptive stimulus, induces analgesia (15, 35), and is thus more likely to induce opioid release. These differences do not eliminate the possibility that opioids are involved in stress-induced respiratory plasticity but prevent us from eliminating the potential contribution of other neural mechanisms.

The fact that immobilization stress affected only the hypercapnic ventilatory response suggests, albeit indirectly, that previous stress exposure affected neural pathways involved in the hypercapnic, but not the hypoxic, response. Recent neuroanatomic data provided by Berquin et al. (4) are consistent with this idea. These authors mapped neuronal populations expressing the protein Fos after exposure to moderate hypoxia (FIO2 = 0.11) or hypercapnia (FICO2 = 0.05). Their results revealed important differences in the pattern of Fos expression between the two ventilatory stimuli. A key feature is the demonstration that hypercapnia, but not hypoxia, increased Fos immunoreactivity in the locus coeruleus (LC) and the paraventricular nucleus of the hypothalamus (PVH), two structures that play critical roles in the coordination of the stress response (for review see Refs. 11 and 18). Local acidification of noradrenergic neurons of the LC increases respiratory frequency and phrenic nerve discharge in cats (10). Moreover, intrinsic activity of LC neurons is exquisitely sensitive to hypercapnia (37), and exposure to CO2 increases Fos immunoreactivity in several brain stem noradrenergic regions, including the LC (4, 17, 40). Noradrenergic LC neurons therefore appear to be an important part of the hypercapnic ventilatory response (17). Although the role of the PVH in ventilatory control is less documented, neuroanatomic tracing studies suggest a direct connection between the PVH and phrenic (inspiratory) motoneurons (42). Moreover, the same study showed that chemical activation of the PVH increases diaphragmatic electromyogram activity (42). Nonetheless, the sum of these data raises the possibility that the LC and PVH may be part of a parallel pathway in the neural control of breathing that acts at the interface between systemic (chemosensory) and processive (psychological) influences on respiratory motor behavior.

Stress and the hypoxic ventilatory response. Whether expressed as absolute values or percent change from baseline, none of the ventilatory variables measured under the hypoxic condition were significantly affected by previous stress exposure. We have retained three possible explanations for the lack of stress-induced changes in the short-term hypoxic ventilatory response. First, a stronger hypoxic stimulus may have revealed differences in the hypoxic ventilatory response between stressed and unstressed rats; however, severe hypoxia (i.e., PaO2 < 40 Torr) would raise questions concerning the physiological significance of stress-induced respiratory plasticity. Second, immobilization stress did not affect carotid body function, and, unlike hypercapnia, stress-induced neural plasticity occurred in regions that are not directly relevant to the short-term hypoxic ventilatory response. Finally, because stress affects the serotonergic system (9), immobilization stress may affect other time domains of the hypoxic ventilatory response such as long-term facilitation, a serotonin-dependent manifestation of respiratory plasticity (14, 38). This hypothesis remains to be tested.

Perspectives

Our results showed that exposure to immobilization, a processive stress, attenuates the responsiveness to hypercapnia in rats. This effect was observed after exposure to a relatively mild stress paradigm and a moderate hypercapnic stimulus in an awake animal. These findings have important potential implications to many studies where various forms of stress (including immobilization) may be an inherent part of the experimental protocol. Yet the potential implications of stress in assessment of ventilatory control is often dismissed by most investigators.

The effects of previous stress exposure on ventilation are likely to be more notable when respiratory drive is further reduced, such as during sleep or anesthesia. This hypothesis is consistent with the irregular nocturnal breathing pattern observed in patients suffering from stress-related neurological diseases, such as panic disorders, which also show an increased rate of apneas compared with healthy subjects (39). The functional significance of stress-induced attenuation of hypercapnic responsiveness as a manifestation of respiratory plasticity remains unclear but may be part of a more general strategy aimed at attenuating the deleterious effects of stress.


    ACKNOWLEDGEMENTS

We thank Drs. Guy Drolet and Aida Bairam for helpful discussions and critical reading of earlier drafts of the manuscript.


    FOOTNOTES

R. Kinkead is a Parker B. Francis Fellow in Pulmonary research. N. Valois was a Burroughs Wellcome scholar. This study was supported by the Fonds de la Recherche en Santé du Québec through a Young Investigator Award to R. Kinkead.

Some of these results have been reported in abstract form (21).

Address for reprint requests and other correspondence: R. Kinkead, Centre de Recherche, CHUQ, Hôpital St-François d'Assise (D0-711), 10 rue de l'Espinay, Québec, PQ, Canada G1L 3L5 (E-mail: Richard.Kinkead{at}crsfa.ulaval.ca).

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.

Received 27 October 2000; accepted in final form 20 December 2000.


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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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J APPL PHYSIOL 90(5):1729-1735
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