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J Appl Physiol 81: 1627-1632, 1996;
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Journal of Applied Physiology
Vol. 81, No. 4, pp. 1627-1632, October 1996
CONTROL OF BREATHING, CIRCULATION, AND TEMPERATURE

Effect of prior O2 breathing on ventilatory response to sustained isocapnic hypoxia in adult humans

Y. Honda, H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama

Departments of Physiology, Anesthesiology, and Chest Medicine, School of Medicine, Chiba University, and Department of Physical Therapy, International University of Health and Welfare, Ohdawara 324, Japan

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES

ABSTRACT

Honda, Y., H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. Effect of prior O2 breathing on ventilatory response to sustained isocapnic hypoxia in adult humans. J. Appl. Physiol. 81(4): 1627-1632, 1996.---Sixteen healthy volunteers breathed 100% O2 or room air for 10 min in random order, then their ventilatory response to sustained normocapnic hypoxia (80% arterial O2 saturation, as measured with a pulse oximeter) was studied for 20 min. In addition, to detect agents possibly responsible for the respiratory changes, blood plasma of 10 of the 16 subjects was chemically analyzed. 1) Preliminary O2 breathing uniformly and substantially augmented hypoxic ventilatory responses. 2) However, the profile of ventilatory response in terms of relative magnitude, i.e., biphasic hypoxic ventilatory depression, remained nearly unchanged. 3) Augmented ventilatory increment by prior O2 breathing was significantly correlated with increment in the plasma glutamine level. We conclude that preliminary O2 administration enhances hypoxic ventilatory response without affecting the biphasic response pattern and speculate that the excitatory amino acid neurotransmitter glutamate, possibly derived from augmented glutamine, may, at least in part, play a role in this ventilatory enhancement.

normocapnia; mild hypoxia; glutamine-glutamate system

INTRODUCTION

THE VENTILATORY RESPONSE to isocapnic sustained hypoxia is known to exhibit a biphasic profile (5, 23): an initial rapid rise followed by a gradual decline. The former is induced by an excitation of the peripheral chemoreceptors, but the mechanism for the latter remains to be elucidated (21). Interestingly, regarding the secondary depression (defined as biphasic hypoxic ventilatory depression, HVD), it has been suggested by several investigators that its magnitude is in some way also determined by a centrally mediated input from the peripheral chemoreceptors (3, 7, 10, 11, 13).

The presence of peripheral chemoreceptor activities during ambient air breathing in humans at sea level has been well established to be in the range of 10-20% of the resting ventilation (4, 22). Accordingly, the presence of HVD in room air breathing is also speculated, and this was defined as "ambient air HVD" (15). In fact, Easton et al. (6) found that enhanced HVD by repeated hypoxic challenges was progressively resolved by increasing O2 concentration in the preceding inspired air. We therefore attempted to determine whether prior O2 breathing can resolve ambient air HVD and modify the profile of biphasic HVD in this study.

Hyperoxic hyperventilation was first demonstrated in carotid-deafferented and conscious cats by Miller and Tenney (18). Gautier et al. (9) also observed in cats that the degree of hyperpnea was augmented after carotid body denervation and made the interpretation that hyperoxia-induced inhibitory afferent information from the carotid body was lost after chemodenervation. They also ascertained that the effect of this central stimulation disappeared as a result of anesthesia. Recently, Becker et al. (2) demonstrated a substantial increase in minute ventilation during normocapnic hyperoxia in healthy humans and that hyperpnea lasted for >15 min after the termination of hyperoxic exposure. This suggests that some humoral agents might be responsible for long-lasting ventilatory stimulation.

METHODS

Sixteen young college students (11 women and 5 men) participated in the study. Their age, height, and body weight (means ± SD) were 21.2 ± 2.2 yr, 161.5 ± 6.8 cm, and 54.9 ± 5.3 kg, respectively. Informed consent was obtained from each subject, and the study protocol was approved by the local ethics committee.

Two experimental procedures were carried out.

Experiment I: measurement of ventilatory responses. The subject was connected to a one-way respiratory valve through a mouthpiece and a hot wire flowmeter (Minato Medical Scientific, Tokyo, Japan). The respiratory valve was placed within a closed circuit of ~5-liter capacity to which a bypass tube containing a CO2 absorber was connected via a three-way stopcock (stopcock 1); two other three-way stopcocks (stopcocks 2 and 3) were placed on opposite sides of the respiratory valve. In the beginning, stopcock 1 was closed to the CO2 absorber and stopcocks 2 and 3 were open to room air, and thus the subject was breathing room air until a steady state was attained. Then room air or 100% O2 was inhaled in random order through stopcock 2 and exhaled from stopcock 3 for 10 min. To avoid the possibility that the maneuver for administering the different gases was noticed by the subject, a screen was placed between the subject and stopcocks 2 and 3. The subject was breathing room air again for ~5 min, during which a rubber bag containing ~10 liters of a 9% O2 gas mixture was connected to stopcock 3 and another bag containing ~10 liters of N2 gas was connected to stopcock 2. Then, by operating these stopcocks, the subject first breathed N2 gas, and end-tidal PO2 (PETO2) quickly decreased to ~50 Torr within 0.5 min, and subsequently the 9% O2 gas mixture was rebreathed and arterial O2 saturation measured with a pulse oximeter (Biox III, Ohmeda; defined as SpO2) rapidly declined to 80%. Usually this condition was attained within ~3-4 min. During this procedure, end-tidal PCO2 (PETCO2) was maintained at a normocapnic level by adjustment of stopcock 1. This condition was usually achieved within 4-5 min. PETO2 and SpO2 were maintained at constant levels by managing the rate of O2 inflow introduced through a small tube inserted just before the inspiratory inlet of the respiratory valve. This sustained hypoxic condition lasted for 20 min. PETO2, PETCO2, and SpO2 levels over this time course are illustrated in Fig. 1. The ventilatory studies conducted with prior O2 and room air breathing were defined as +O2 and -O2 runs, respectively. In each subject, two runs were conducted at >4-h intervals.
Fig. 1. Time course of changes in average end-tidal PCO2 (PETCO2), end-tidal PO2 (PETO2), and arterial O2 saturation measured by pulse oximeter (SpO2) during sustained isocapnic hypoxia in 16 healthy subjects. square , -O2 run; bullet , +O2 run. Error bars, SE. Pre, value before hypoxic challenge. Steady-state normocapnic-hypoxic condition was attained at ~4 min in PETCO2 and 3 min in PETO2 and SpO2.
[View Larger Version of this Image (12K GIF file)]

PETCO2 and PETO2 were continuously monitored and recorded by a rapid-response gas analyzer (model 1H 21, Sanei, Tokyo, Japan). In addition, tidal volume (VT) and SpO2 (obtained by a hot wire flowmeter with its integrator and the pulse oximeter, respectively) were also continuously and simultaneously recorded on a thermal array recorder (Nihon Kohden, Tokyo, Japan). From these recordings, respiratory frequency and inspiratory minute ventilation (VI) were calculated.

Experiment II: chemical analysis of blood plasma. Just before the beginning of sustained hypoxia in +O2 and -O2 runs, 10 ml of venous blood were withdrawn from 10 of the 16 subjects. Plasma concentrations of the following chemicals were analyzed: beta -endorphin, epinephrine, norepinephrine, dopamine, serotonin, gamma -aminobutyric acid, glutamine, glutamic acid, and glycine. Methods of measurement were radioimmunoassay for beta -endorphin and high-performance liquid chromatography for the others. Statistical analysis was performed using Student's paired t-test to compare the results of +O2 and -O2 runs. Multiple regression analysis was also performed between ventilatory responses and measured chemical agents.

RESULTS

As shown in Fig. 1, the steady-state condition of normocapnic hypoxia was attained at about the 4th min of hypoxic challenge. Table 1 shows the sequential changes in VT, respiratory frequency, and VI. VI was significantly augmented to a greater degree in the +O2 than in the -O2 run after the 5th min. Because VT elevation was significantly higher in the +O2 than in the -O2 run after the 5th min whereas no statistical difference in respiratory frequency response was seen between the two runs except at the 15th min, the difference in VI augmentation was largely due to altered VT response. The time course of average VI is illustrated in Fig. 2. In +O2 and -O2 runs, peak ventilatory responses were seen between the 5th and 7th min, then gradually declined in almost parallel fashion. Accordingly, despite the substantial augmentation of hypoxic hyperventilation in the +O2 run, the general features of biphasic HVD appeared nearly unchanged by prior O2 breathing. Figure 3 compares the magnitude of maximal VI increment from the control level as well as biphasic HVD from the maximal VI between the +O2 and -O2 runs. In both runs, the latter was just ~50% of the former.

Table 1. Sequential changes in hypoxic ventilatory responses to sustained isocapnic hypoxia during 20 min

Before Hypoxia Hypoxia
5 min 7 min 10 min 15 min 20 min
VT, ml
  +O2 run 660 ± 174  1,052 ± 347  1,075 ± 387  944 ± 300  964 ± 291  881 ± 244 
  -O2 run 629 ± 211  899 ± 336  892 ± 387  863 ± 288  795 ± 238  796 ± 250 
  Delta 31 ± 115  154 ± 190dagger 183 ± 219dagger 80 ± 138* 116 ± 178* 85 ± 128*
f, breaths/min
  +O2 run 14.4 ± 3.8  19.8 ± 7.1  19.7 ± 6.4  18.4 ± 5.9  19.3 ± 6.0  19.5 ± 6.0 
  -O2 run 13.8 ± 4.8  18.4 ± 7.5  18.5 ± 7.8  17.5 ± 7.1  16.7 ± 5.4  18.1 ± 6.8 
  Delta 0.5 ± 4.0  1.6 ± 3.7  1.6 ± 3.8  0.9 ± 3.7  2.6 ± 3.4dagger 1.4 ± 2.9 
 VI, l/min
  +O2 run 9.54 ± 2.37  21.87 ± 12.91  21.65 ± 9.62  17.49 ± 6.75  17.84 ± 7.98  17.12 ± 6.91 
  -O2 run 8.84 ± 2.94  16.72 ± 7.89  16.46 ± 7.90  14.71 ± 7.14  13.26 ± 5.45  13.98 ± 6.32 
  Delta 0.93 ± 2.22  5.15 ± 8.93* 4.91 ± 7.01* 3.23 ± 5.44* 4.65 ± 6.18dagger 3.14 ± 3.93dagger
Values are means ± SD. VT, tidal volume; f, respiratory frequency; VI, minute ventilation; Delta , difference between +O2 and -O2 runs. * and dagger Significant at 5% and 1% levels, respectively.

Fig. 2. Time course of changes in inspiratory minute ventilation (VI). VI in +O2 run significantly exceeded that in -O2 run from 5th min of hypoxia. Biphasic hypoxic ventilatory depression was almost parallel in +O2 and -O2 runs.
[View Larger Version of this Image (12K GIF file)]

Fig. 3. Comparison of maximal increment in VI and magnitude of biphasic hypoxic ventilatory depression (HVD) between -O2 and +O2 runs. Values are means ± SE. Although absolute magnitudes were much larger in +O2 than in -O2 run, relative magnitude of biphasic HVD against maximal increment was ~50% in both runs.
[View Larger Version of this Image (16K GIF file)]

Enhanced hypoxic hyperventilation was accompanied by stronger dyspnea sensation in six +O2 runs than in the -O2 runs, whereas the opposite occurred in four subjects. The remaining six subjects did not experience any difference between the two runs.

PETCO2 levels with room air breathing just before the hypoxic challenge were 39.6 ± 3.8 and 38.1 ± 3.7 Torr in the -O2 and +O2 run, respectively. PETCO2 was significantly depressed by prior O2 breathing, indicating the presence of residual hyperventilation after O2 breathing.

The results of chemical analysis are represented in Table 2. Among the nine chemical agents measured in blood plasma, a significant finding in relation to hypoxic ventilatory responses was observed only for glutamine. Figure 4, top, shows no significant relationship between plasma glutamine concentration and the maximal increment in hypoxic ventilatory response or magnitude of biphasic HVD. However, as demonstrated in Fig. 4, bottom, when these variables were expressed in terms of the difference between the +O2 and -O2 runs, the relationship between VI and glutamine increment became significant (r = 0.69). This was considered to signify that enhanced hypoxic hyperventilation after O2 breathing may have been induced from an increased level of glutamine. Multiple regression analysis between the change in maximal VI and other chemicals also confirmed the significant contribution of glutamine in their relationships. In the case of the change in the biphasic HVD-glutamine relationship, the correlation coefficient improved from 0.11 to 0.48 but remained insignificant.

Table 2. Plasma concentration of chemical agents just before sustained hypoxic challenge in +O2 and -O2 runs

Subject
SO
TH
ST
MH
SK
HK
NS
MM
SW
TD
 -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2  -O2 +O2
 beta -Endorphin, pg/ml 10 18 13 18 21 23 13 11 7 9 11 10 8 16 11 8 21 23 11 9
Epinephrine, pg/ml 29 29 32 37 41 24 8 15 19 13 25 33 23 29 18 14 50 65 42 38
Norepinephrine, pg/ml 326 202 171 173 291 308 115 144 187 167 204 152 162 152 157 161 360 351 207 171
Dopamine, pg/ml 17 16 >10 >10 >10 11 >10 >10 10 >10 >10 >10 >10 >10 >10 >10 17 >10 >10 11
Glutamine, µmol/dl 60.0 57.7 52.2 55.6 53.1 55.4 45.9 42.7 47.5 47.3 41.1 47.5 45.5 45.1 52.7 57.0 49.6 49.4 61.9 58.3
Serotonin, ng/ml 159 148 142 126 90 67 195 206 232 248 72 83 88 85 93 86 106 101 76 85
GABA, pmol/ml 142 131 120 118 121 135 137 149 176 173 367 135 121 156 171 175 212 116 139 149
Glutamic acid, µmol/dl 4.9 3.7 3.3 3.7 5.7 5.1 2.2 2.7 3.1 3.2 2.9 2.6 2.7 2.9 3.5 3.2 5.4 5.2 2.8 3.0
Glycine, µmol/dl 20.6 18.9 19.5 20.8 24.9 25.1 18.4 18.5 20.4 19.2 26.4 26.6 16.5 17.3 27.0 25.2 14.8 14.3 26.1 24.1

Fig. 4. Relationship between maximal increment in hypoxic hyperventilation (left) and amount of biphasic HVD (right) vs. plasma glutamine concentration. Top: absolute magnitude; bottom: differences (Delta ) between +O2 and -O2 runs. Relationship between maximal increment of hypoxic ventilation and glutamine concentration in terms of difference from +O2 to -O2 run became significant at 5% level (bottom left).
[View Larger Version of this Image (20K GIF file)]

DISCUSSION

We have shown that hypoxic ventilatory responses with preceding O2 breathing were markedly augmented but that the general profile of biphasic HVD remained nearly unchanged (Fig. 2). Several studies (2, 9, 15, 18) have reported ventilatory augmentation during hyperoxia. To our knowledge, however, this is the first finding that the effect of enhanced ventilatory activity induced by O2 breathing still appeared to have effectively elevated the subsequent ventilatory response to sustained hypoxia.

Nature of augmented hyperoxic hyperventilation in the previous studies. In 1975, Miller and Tenney (18) reported in unanesthetized cats that breathing 400-450 Torr arterial PO2 induced no significant ventilatory change before carotid chemodeafferentation but resulted in a 16% elevation (P < 0.05) in ventilation with significant arterial PCO2 depression (mean 8.7 Torr) after the operation. The hyperventilation developed gradually, attaining a peak at 3.5 min of hyperoxic exposure. Subsequently, Gautier et al. (9) confirmed the presence of hyperoxic hyperventilation in conscious cats with carotid body denervation. They further found that anesthesia abolished this hyperpneic response. PETCO2, however, significantly decreased before (1.3 ± 0.3 Torr) and even more after (4.7 ± 0.8 Torr) carotid chemodenervation in these conscious cats. They reasoned that the enhanced ventilatory response can be ascribed to a loss of inhibitory afferent discharges from the peripheral chemoreceptors after chemodenervation.

Recently, Becker et al. (2) reported a 60% elevation in average ventilation in nine healthy conscious humans breathing 50% O2 while PETCO2 was adjusted at a normocapnic level. Furthermore, after 15 min of recovery time, they observed that ventilation was still augmented by 33% above the baseline.

These investigations indicate that hyperoxic hyperventilation may be of central origin, because it can be seen only in a conscious state, that diminished afferent input from the peripheral chemoreceptors due to hyperoxia enhances hyperpnea, and that its magnitude is PETCO2 dependent. Furthermore, the maintenance of normocapnia induces apparent and substantial hyperventilation, and there must be humoral origin for ventilatory augmentation, because it develops gradually during O2 breathing and lasts for >15 min after termination of hyperoxia. Also, augmented ventilation in all these studies was ascribed mainly to increased VT, and respiratory frequency showed no statistically significant change.

Nature of hypoxic hyperventilation followed by O2 breathing in the present study. The fact that larger hypoxic ventilatory response in the +O2 than in the -O2 run was derived by preliminary O2 administration may be explained by 1) elevated blood as well as tissue PCO2 and H+ stimulations due to decreased cerebral blood flow that was produced during O2 breathing and lasted for some time after its termination or 2) some unknown humoral origin to stimulate ventilation (see above). The first explanation may not apply, because we previously observed that cerebral blood flow in response to a step change in blood gas level attained a steady-state condition up to ~10 min (14). Therefore, the substantial hypoxic hyperventilation that lasted for >20 min in the +O2 run cannot be explained in this way. We then compared the characteristic features of the hyperoxic hyperventilation mentioned above and the hypoxic hyperventilation in our study. Common findings are observed in the conscious condition; they include VT-dependent augmentation in VI and hyperoxic breathing-induced hypocapnia. Accordingly, maintaining a normocapnic condition during sustained hypoxia should have induced more PCO2-dependent ventilatory augmentation in the +O2 than in the -O2 run. These similarities in both types of hyperpnea made us speculate that respiratory changes in our study must have originated from the same humoral agent, possibly produced during hyperoxic hyperpnea.

As represented in Fig. 4, the increment in maximal hypoxic ventilation from the -O2 to the +O2 run was significantly correlated with the difference in plasma glutamine concentration between the two runs. Glutamine is known to be the most potent precursor of the excitatory amino acid neurotransmitter glutamate (12, 16), which stimulates ventilation by altering neuronal excitability centrally. In addition, glutamate-binding sites were found in specific medullary nuclei associated with respiratory activity (8), and the application of glutamate to the ventral medulla resulted in prompt and dose-dependent increases in VT (19). Furthermore, Li and Nattie (17) recently demonstrated long-lasting augmented ventilation by stimulating the metabotrophic glutamate receptors in the brain stem retrotrapezoid nucleus region, which is claimed by this group to be the most potent CO2-chemosensitive area (20). Although the measured glutamate concentration in plasma was too small to allow assessment of a definite tendency and its actual concentration in the brain could not be measured, we assumed that the difference in glutamine concentrations between the +O2 and -O2 runs might reflect the glutamate level in plasma and the affected site in the brain. On the basis of this assumption, we speculated that the glutamine-glutamate system might be responsible, at least in part, for the augmented hypoxic hyperventilation induced by prior O2 breathing.

Figure 4, bottom left, indicates that plasma glutamine was clearly diminished in three subjects and nearly unchanged in three other subjects by the +O2 run. This may signify that possibly the activated glutamine-glutamate system is not the sole cause for hypoxic hyperventilation observed in this study. Figure 4 also indicates less maximal increment in hypoxic hyperpnea in the +O2 than in the -O2 run (negative change in maximal VI) in four subjects. This does not mean that total VI is less in the +O2 than in the -O2 run, because, as can be seen from Fig. 2, ventilation in the +O2 run shows a tendency to shift upward before hypoxic challenge. In these four subjects the VI increment in the prehypoxic period was substantial, so that the increment of hypoxic hyperventilation may have not exceeded the one in the -O2 run.

Nature of biphasic HVD. Figures 2 and 3 demonstrate that although preliminary O2 administration shifted the ventilatory level upward, the general features of biphasic HVD appeared nearly unchanged. The relative magnitude of ventilation in the initial rapid increment and in the subsequent gradual decrement were the same in the +O2 and -O2 runs. This may signify that the chemical agent possibly generated by O2 breathing is different from the one possibly produced during sustained hypoxia. Another possibility may be that the mechanism responsible for biphasic HVD is a nonchemical process, such as the adaptation of chemoreceptor activities (1). In any event, our assumption that eliminating ambient air HVD by O2 breathing could modify the profile of biphasic HVD was not realized in this study.

In conclusion, prior O2 breathing induced marked augmentation of ventilatory responses to sustained normocapnic hypoxia. This augmentation was associated with an increase in the level of plasma glutamine. Glutamine is the major metabolic precursor of the excitatory amino acid neurotransmitter glutamate, a substance that has been known to augment ventilation when applied centrally. Thus it is possible that enhanced glutaminergic activity may explain the augmented HVR and the hyperventilation produced by hyperoxia. Although the ventilatory response to hypoxia was augmented by preliminary O2 administration, the profile of the biphasic ventilatory decline was not modified in terms of relative magnitude, suggesting that separate mechanisms may explain these two opposing ventilatory responses to hypoxia.

FOOTNOTES

Address for reprint requests: Y. Honda, Omiyadai 4-26-17, Wakaba-Ku, Chiba, 264 Japan.

Received 5 December 1995; accepted in final form 13 May 1996.

REFERENCES

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8. Gatti, P. J., A. M. Taveira Da Silva, P. Hamosh, and R. A. Gillis. Cardiorespiratory effects produced by application of L-glutamic acid and kainic acid to the ventral surface of cat hindbrain. Brain Res. 330: 21-29, 1985.
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0161-7567/96 $5.00 Copyright © 1996 the American Physiological Society


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