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1 Departmento De Ciencias Biologicas y Fisiologicas/IIA, Universidad Peruana Cayetano Heredia, Lima 100, Peru; and 2 University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Peripheral chemoreflex function was studied in high-altitude (HA) natives at HA, in patients with chronic mountain sickness (CMS) at HA, and in sea-level (SL) natives at SL. Results were as follows. 1) Acute ventilatory responses to hypoxia (AHVR) in the HA and CMS groups were approximately one-third of those of the SL group. 2) In CMS patients, some indexes of AHVR were modestly, but significantly, lower than in healthy HA natives. 3) Prior oxygenation increased AHVR in all subject groups. 4) Neither low-dose dopamine nor somatostatin suppressed any component of ventilation that could not be suppressed by acute hyperoxia. 5) In all subject groups, the ventilatory response to hyperoxia was biphasic. Initially, ventilation fell but subsequently rose so that, by 20 min, ventilation was higher in hyperoxia than hypoxia for both HA and CMS subjects. 6) Peripheral chemoreflex stimulation of ventilation was modestly greater in HA and CMS subjects at an end-tidal PO2 = 52.5 Torr than in SL natives at an end-tidal PO2 = 100 Torr. 7) For the HA and CMS subjects combined, there was a strong correlation between end-tidal PCO2 and hematocrit, which persisted after controlling for AHVR.
regulation of ventilation; hypoxic ventilatory response; human; Andean natives; hyperoxia; dopamine; somatostatin; blunting
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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HIGH-ALTITUDE (HA) NATIVES resident at HA breathe harder and have a lower end-tidal PCO2 (PETCO2) than sea-level (SL) natives resident at SL. On traveling to HA, SL natives also lower their PETCO2 in a process of ventilatory acclimatization that occurs over a number of days. However, at a more fundamental level, respiratory control in HA natives at HA is dissimilar from that in SL natives at HA. On the one hand, SL natives acclimatized to HA possess an acute ventilatory sensitivity to hypoxia (AHVR) that is elevated substantially above its value at SL (5, 21). HA natives resident at HA, on the other hand, have values for AHVR substantially below those for SL natives resident at SL (5, 11, 14, 18, 23-25). Although alterations in carotid body physiology have not been proven to be the cause of the low values for AHVR in HA natives resident at HA, it is, nevertheless, noteworthy that the carotid bodies of HA natives are greatly hypertrophied (1).
In HA natives at HA, brief exposure to hyperoxia, lasting a few breaths
for seconds, results in a slight fall in ventilation (
E) (11, 14), but slightly longer
exposures of a few minutes appear to result in an increase in
E and reduction in
PETCO2 (7, 11, 12).
These results suggest that, in HA natives at HA, any reduction in
respiratory drive from the carotid bodies that occurs in response to
hyperoxia is more than offset by other (central) stimulatory effects of
hyperoxia. However, chronic elevations in oxygen tension have different
effects. In particular, HA natives who come to reside at SL develop
values for PETCO2 that are normal for SL natives at SL (16), which implies that HA natives
at HA only maintain values of
PETCO2 below those associated for
humans at SL because of ongoing stimulation by hypoxia.
This combination of results obtained from short-term and chronic elevations in oxygen tension leaves it unclear as to why HA natives breathe harder at HA than at SL. On the one hand, the results with acute hyperoxia suggest that the stimulatory effects of hypoxia at the carotid body in HA natives are more than outweighed by the reduction in central stimulation, but, on the other hand, continuing hypoxia is clearly required for HA natives to ventilate more at HA than at SL. One possible way of reconciling these observations is that, in HA natives at HA, there is a tonic stimulation arising from the (hypertrophied) carotid body that is unaffected by acute exposures to hyperoxia and can only be removed by chronic exposure to higher levels of oxygen.
This study aims to examine these issues. First, it seeks to confirm
that the difference in AHVR between SL natives at SL and HA subjects at
HA is present in our subjects. Second, the study seeks to determine
whether, in the same group of subjects at a regulated
PETCO2, hyperoxia induces a rapid
initial fall in E followed by a slower progressive
rise in E to values above those observed in hypoxia.
Third, the study seeks to determine whether, under conditions of
poikilocapnic hyperoxia, there is any residual tonic stimulation
arising from the carotid body. Fourth, the study seeks to compare,
using dopamine (DA) and somatostatin (ST) as inhibitors of the carotid
body, the level of peripheral stimulation arising from the carotid body
in HA natives at their ambient end-tidal PO2
(PETO2) with that arising from the
carotid body of SL natives at both their ambient
PETO2 and a level of
PETO2 to match that of HA natives.
A subset of HA natives develops chronic mountain sickness (CMS).
Although the primary finding in these patients is one of excessive
polycythemia, they differ from HA natives with respect to respiratory
control. In particular, compared with healthy HA natives at the same
altitude, patients with CMS are relatively hypoxic and hypercapnic
(10, 23) and may (23) or may not (10) have lower ventilatory sensitivities to hypoxia. A
further aim of this study was to elucidate the differences between the peripheral chemoreflex responses of patients with CMS and those of
healthy HA natives. First, the study compares values for AHVR between
HA natives and patients with CMS by using both a protocol involving
only mild hypoxia and a protocol in which the level of hypoxia is
significantly greater than ambient for these subjects. Second, the
study examines whether the response to hyperoxia differs in CMS
patients compared with control HA subjects. Third, the study examines
the effects of DA and ST to determine whether there are any differences
between the CMS patients and healthy HA natives in the degree to which
E may be stimulated by carotid body activity at
different levels of PO2.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
The HA natives (defined as those who have spent their life at >3,500 m) and patients with CMS (hematocrit >63%) were recruited in Cerro de Pasco, Peru (altitude 4,300 m; barometric pressure at laboratory of 450 mmHg; C. Monge, personal communication). The SL controls were recruited in Lima, Peru from within a group of subjects whom we had previously studied (6). The original plan had been to recruit 25 subjects from each group and undertake all of the protocols on precisely the same subjects. However, because of the extended time period over which this study took place, this was not always possible. In cases in which subjects were no longer available, additional subjects were recruited to keep the total number of subjects studied at the target level. Average values for the physical characteristics for all subjects studied within each of the three groups are given in Table 1. The actual number of subjects common to any pair of protocols is given in Table 2.
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Protocols
A considerable number of protocols were employed in these experiments. The protocols included measurements of AHVR, measurement of the response to hyperoxia, measurements of the response to low-dose DA infusion, and measurements of the response to an infusion of ST. The infusions of drugs were made against a range of different backgrounds of chemical stimulation. For most protocols, we attempted to have 25 subjects in each group in which it was undertaken. However, we had limited supplies of ST, and for these protocols 10 subjects in each group were studied. For every subject studied, we attempted to ensure that a measurement of AHVR had been obtained, and for this reason there may be more than 25 measurements of AHVR in a group.Measurements of AHVR.
These protocols sought to determine AHVR from a set of fairly
rapid manipulations of PETO2,
against which slower variations in E due to other
effects of varying oxygenation should have a limited effect.
Measurements of AHVR were made according to the protocol of Mou et al.
(19). The values for
PETCO2 were held at 2 Torr above
the subjects' ambient air-breathing
PETCO2 throughout the protocol.
PETO2 was held at 100 Torr for 5 min and then decreased in a series of seven steps, with each step lasting 50 s, from an initial
PETO2 of 100 Torr to a final
PETO2 of 45 Torr (the protocol is
denoted as AHVR-45 to reflect this). The decrements of
PETO2 were calculated to provide
approximately equal reductions in arterial saturation at each step and,
therefore, an approximately linear rise in E with time.
Ventilatory responses to hyperoxia. These protocols took place against a background PETCO2 that was 2 Torr above the subjects' normal values for PETCO2 when breathing ambient air. For the first 10 min, PETO2 was held at 52.5 Torr. PETO2 was then abruptly raised to 200 Torr and maintained at that level for 20 min. Finally, PETO2 was returned to 52.5 Torr for the last 10 min of the protocol. The protocol is denoted by the abbreviation HiO2.
Ventilatory responses to DA and ST infusions in hyperoxia. The purpose of these protocols was to determine whether any residual stimulation from the peripheral chemoreceptors in hyperoxia could be detected in HA natives and patients with CMS by infusion of low-dose DA, which is known to inhibit carotid body-mediated responses in humans. The same protocol was undertaken in SL natives to act as a control. PETCO2 was left unregulated in these protocols to avoid any stimulation arising at the carotid body through this procedure.
For all three groups, PETO2 was held at 200 Torr for 30 min. For the first 10 min, no infusion of DA was given; for the second 10 min, an infusion of DA at 3 µg · kg
1 · min1
was administered. This was then stopped while the subject continued to
breathe the hyperoxic gas mixture for the final 10 min with no
infusion. Protocols involving DA are abbreviated as DA-x,
where x indicates the background level of
PETO2 employed, e.g., DA-200 for
this protocol.
Ten SL subjects also undertook this protocol with a 10-min infusion of
ST (0.5 mg/h) replacing the infusion of DA. This protocol was to check
whether, in normal SL subjects, the effects of a ST infusion under
hyperoxic conditions differed in any way from a low-dose infusion of
DA. Protocols involving ST are abbreviated as ST-x, where
x indicates the background level of
PETO2 employed.
Ventilatory responses to DA and ST infusions in euoxia and hypoxia. The purpose of these protocols was to try to determine the degree of reflex ventilatory stimulation arising from the carotid body at an approximately ambient PETO2 (of 52.5 Torr) for the HA natives and patients with CMS. These protocols, using pharmacological inhibitors, provide an alternative to variations in PO2 for examining carotid body function in these subjects. Two sets of control experiments were performed on the SL subjects. One set was at a PETO2 of 100 Torr, which is approximately ambient for the SL natives, and a second set was undertaken at a PETO2 of 52.5 Torr to match the experimental PETO2 used for the HA natives and patients with CMS.
For these experiments (in contrast to the drug infusions in hyperoxia), PETCO2 was regulated throughout at 2 Torr above the subjects' ambient air-breathing level. The PETO2 was held at the appropriate level (either 52.5 or 100 Torr) for 30 min. The infusion, either DA or ST, was conducted over the central 10-min period, with 10-min control periods with no infusion on either side of this. The protocols were denoted in the same style (either DA-x or ST-x, where x indicates the background PETO2) as for the experiments involving infusions of DA and ST in hyperoxia.Apparatus and Techniques
Respiratory measurements and control. During the protocols, the subjects sat upright in a chair and breathed gas via a mouthpiece while they wore a nose clip. The subjects' respired volumes were sensed by using a turbine-style volume sensor (VMM 400, Interface Associates, Laguna Niguel, CA). Their respired gas was sampled and analyzed continuously for PCO2 and PO2 by using a Datex Normocap-Oxy gas analyzer (Datex Ohmeda, Hatfield, UK), which had been modified to remove the normal hourly automatic zeroing. Data were logged to a portable personal computer equipped with National Instruments interface cards (types DAQCard-1200 and DAQCard-AO-2DC, Austin, TX).
The end-tidal gas profiles specified in the protocols were generated by using the end-tidal forcing technique (20). In this technique, a cardiorespiratory model is run to predict the inspiratory PCO2 and PO2 profile that will generate the desired PETCO2 and PETO2, respectively, on a second-by-second basis. When the experiment is started, a computer controlling a fast gas-mixing system mixes and adjusts these inspiratory gases on a second-by-second basis. To allow for the fact that the prediction will not be perfect (and will differ from subject to subject), the computer modifies the actual inspiratory gas mixture by using feedback from the measured end-tidal gases as they become available on a breath-by-breath basis. The real-time control software was completely integrated with the data-acquisition software and was implemented by using the National Instruments LabView software package. The fast gas-mixing system was constructed by using commercially available mass flow controllers (type 1559A, MKS Instruments, Altringham, UK).Drug infusions.
The dose employed for the DA infusion was 3 µg · kg1 · min1.
The ST (somatostatin acetate, UCB) was dissolved in saline to a concentration of 0.05 mg/ml and infused at the rate of 0.5 mg/h. To
avoid problems with adsorption of ST, the infusion catheter was kept as
short as possible, and the infusion was run for 30 min and discarded to
waste before it was connected to the subject.
Data Analysis
AHVR.
Two methods were employed to obtain numerical estimates for AHVR from
the data. In the first method, averages were obtained for
E and PETO2 from
the last 20 s of each 50-s step. The values for
PETO2 were transformed into
calculated values for saturation with the use of the equation of
Severinghaus (22). A linear regression was then performed
between E and arterial saturation to produce a
slope (SAHVR) and an intercept
(KAHVR). SAHVR provides a
measure of AHVR, and KAHVR provides an
extrapolation for E in the absence of hypoxia.
c that is equivalent to KAHVR as a
measure of hypoxia-independent E.
Hyperoxic responses.
For each subject, the breath-by-breath data from this protocol were
averaged into 1-min time bins. These 1-min averages were then averaged
for each of the subject groups to produce plots of the average
responses for the groups. In addition to this, certain time points
[E(x), where x is the minute
average] for individual subjects were used to calculate the following
indexes for the hyperoxic response
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Infusions of DA and ST.
The data from these protocols were averaged into 1-min periods, as for
the hyperoxic responses. From these, average plots were produced for
each of the subject groups. The response to the drug was estimated as
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Statistics. The statistical analysis of the results was conducted principally through ANOVA, details of which are given in the RESULTS section. Where comparisons were drawn within groups, subjects were included as a random factor. Post hoc comparisons were undertaken by using the least squared difference technique, which makes allowance for the total number of comparisons that have been drawn. Correlations between variables were assessed by using product-moment correlation. Statistical significance was accepted at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
From the data in Table 1, it may be seen that the HA natives were slightly, but significantly, older than the SL natives. They were also shorter and lighter. The patients with CMS were ~10 yr older than the SL controls. As expected, the hematocrits of the CMS patients were significantly higher than those for the HA natives without CMS. A scoring system for the symptoms of CMS (15) was used on a subset of the subjects (n = 32 for HA, n = 25 for CMS), where a value of
12 is taken as
evidence of significant symptomatology. For HA subjects, the mean value
was 6.3 ± 5.1 (SD), and, for CMS patients, the mean value was
16.6 ± 3.9. These differences were highly significant
(P < 0.001). In the patients with CMS, ambient
air-breathing PETCO2 was
significantly higher, and PETO2
significantly lower, than in the normal HA natives.
AHVR
The ventilatory responses (averages for the last 20 s of each step of each protocol) of the individuals are shown in Fig. 1 for protocol AHVR-45 and in Fig. 2 for protocol AHVR-34. Also shown are average values across subjects for each protocol and subject group. The individual responses showed marked variation in all three subject groups, although there appeared to be a loss of the high responders in the HA and CMS groups compared with the SL control group. The average ventilatory responses for all subject groups were reasonably linear with calculated saturation, although the SL group exhibited some degree of curvature (concave upward).
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The differences between the techniques of linear regression and dynamic
modeling in providing numerical estimates for AHVR were small, and,
therefore, only the results from the dynamic modeling technique are
presented. Average values for Gp and c (calculated
E in the absence of hypoxia) are given in Table 3. For the protocol AHVR-45, the average
values for Gp for both HA natives and patients with CMS were around
one-third of the value for the SL natives (P < 0.001).
c was significantly greater (P < 0.05) for the
HA natives and patients with CMS than for SL natives (although this may
be an artifactual result arising from extrapolating from the somewhat
curvilinear response of the SL group). The HA natives and patients with
CMS did not differ significantly from each other in any of these
variables for this protocol.
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For patients with CMS, the results from the protocol AHVR-34 (reducing
PETO2 to 34.4 Torr) did not differ
from the results from the protocol AHVR-45. However, for HA subjects
without CMS, protocol AHVR-34 resulted in values for Gp that were
significantly higher (P < 0.01) than those from
protocol AHVR-45. In the case of the HA subjects, but not those with
CMS, a substantial number of the AHVR-34 measurements were undertaken
at a much later date than the AHVR-45 measurements. For these subjects,
the measured ambient PETCO2 was
significantly greater for the AHVR-34 protocols than for the AHVR-45
protocols by an average of 0.78 Torr (95% confidence interval: 
1.40
to 0.16, P < 0.02). It would seem likely that this
systematic difference in estimating ambient
PETCO2 underlies the difference in
AHVR between the AHVR-45 and AHVR-34 protocols for the HA subjects.
This conclusion is supported by the presence of a significant
correlation (r = 0.42, P < 0.01) between the differences in PETCO2
and the differences in value for Gp. The values for Gp for the HA
subjects from the AHVR-34 protocol were also significantly higher than
those for the CMS group of subjects from either protocol
(P < 0.05).
Ventilatory Responses to Hyperoxia
The ventilatory responses to hyperoxia (protocol HiO2) are illustrated in Fig. 3.E, PETCO2, and
PETO2 are shown, averaged for each
subject group, at 1-min intervals throughout the protocol. The mean
values for PETCO2 and
PETO2 suggest that these values have been reasonably well controlled for much of the protocol, although
there are some minor imperfections in the
PETCO2 control at the onset and
offset of hyperoxia.
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Over the first part of the initial 10-min period before the induction
of hyperoxia, there was a progressive rise in E for the HA natives and patients with CMS, which is consistent with the
elevation of PETCO2 by 2 Torr above
the normal air-breathing value. By way of contrast, for the SL natives,
E fell over this 10-min period, which is consistent
with the development of some degree of hypoxic ventilatory depression
in these subjects.
At the onset of hyperoxia, there was a rapid initial fall in
E in all three subject groups. As expected, this
fall was greatest (P < 0.001) in the SL natives who
have the greatest AHVR and much smaller in the HA natives and patients
with CMS. There was also a smaller difference between the fall in
E for the HA group (larger) and the fall for the CMS
group (smaller), which was statistically significant (P < 0.05). Over the next 20 min, there was a slow progressive rise
in E with the hyperoxic exposure of ~8 l/min, which was similar in all three groups. This rise in
E over time turned the ventilatory response to
sustained hyperoxia into a rise, rather than a fall, in
E for the HA and CMS groups. At the return to
hypoxia, there was a rapid rise in E in all three groups. This was largest for the SL group (P < 0.001),
and in this case the difference between HA subjects (larger rise) and CMS patients (smaller rise) failed to reach statistical significance (P = 0.079). It was noticeable that, for all subject
groups, the rapid rise in E at the offset of
hyperoxia was considerably greater than the rapid fall in
E at the onset of hyperoxia. Numerical values for
these changes are given in Table 3.
Ventilatory Responses to DA and ST Infusions in Hyperoxia
The mean responses for each group to DA infusion in hyperoxia are illustrated in Fig. 4. There does not appear to be any residual stimulation from the carotid bodies in hyperoxia that can be suppressed by DA in any subject category. Numerical values are given in Table 3, none of which differed significantly from zero. The results from the infusion of ST in hyperoxia in SL natives did not differ from the results from infusion of DA in SL natives, nor did the effect of ST differ significantly from zero.
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Ventilatory Responses to DA and ST Infusions in Euoxia and Hypoxia
The dynamics of the ventilatory response to the onset and offset of the infusions of DA and ST are shown in Fig. 4. Numerical values for the effects of these infusions onE are given in Table 3. It is immediately apparent that the effects of both DA and ST
infusion are much greater for the experiments in the SL subjects with a
background PETO2 of 52.5 Torr than
for the other experiments (P < 0.001). These
experiments were removed from the analysis, and the remainder of the
ANOVA was conducted on the SL data at 100 Torr and the HA and CMS data
at 52.5 Torr for the DA and ST experiments combined. This analysis
revealed that DA was somewhat less effective in suppressing
E than ST (ANOVA, P < 0.01) and
that the responses of the SL group were significantly smaller than
those of the combined HA and CMS groups (P < 0.05),
but that the responses of the HA and CMS groups did not differ.
Comparison of Different Measures of Peripheral Chemoreflex Contribution at PETO2 of 52.5 Torr
The peripheral chemoreflex contributions at PETO2 = 52.5 Torr can be calculated from the value for Gp multiplied by the reduction in saturation associated with reducing PETO2 to 52.5 Torr (see Table 3), and these can be compared with the two estimates arising from the hyperoxic step (ONf and OFFf, Table 3) and with the estimates arising from DA and ST infusion (protocols DA-52.5 and ST-52.5). ANOVA revealed that both the factors of subject type (SL, HA, and CMS) and estimate type are significant (P < 0.001), but not the interaction between the two terms. Post hoc testing revealed that the estimates with no preoxygenation (DA and ST infusion and ONf) did not differ from one another, the estimate with modest preoxygenation (derived from the measurements of Gp, where PETO2 = 100 Torr for 5 min before the measurement) was significantly larger than for DA and ONf (although it did not differ significantly from the ST estimates), and that the estimate with marked preoxygenation (OFFf, where PETO2 = 200 Torr for 20 min before the measurement) was significantly greater than all other estimate types. The estimates for the SL group were clearly much larger than for the HA and CMS groups (P < 0.001), and the differences between the HA and CMS groups were marginal (P = 0.077). If the SL data were excluded from the analysis on the grounds that their larger responses were associated with a substantially greater variance, then the difference between the HA group (larger responses) and CMS group (smaller responses) becomes highly significant (P < 0.005).Correlations Among Hematocrit, PETCO2, and AHVR
For the SL, HA, and CMS groups individually, there were no correlations among hematocrit, ambient PETCO2, and the various measures of AHVR that had a greater level of significance than P < 0.01 (there were no measures of hematocrit for the SL group). For the HA and CMS groups combined, there was a strong correlation between hematocrit and ambient PETCO2 (r = 0.50, P < 0.001), and between hematocrit and some measures of AHVR (ONf, r =0.50, P < 0.001;
OFFf, r = 0.43, P < 0.01), but not other measures of AHVR (correlations for measures of
AHVR from protocols AHVR-45, AHVR-34, DA, and ST were all not
significant). There were weaker correlations between ambient
PETCO2 and some measures of AHVR (Gp-34, r = 0.37, P < 0.02;
ONf, r = 0.37, P < 0.05), but correlations between ambient
PETCO2 and the other measures of
AHVR were not significant (although all still negative). The
partial correlation between hematocrit and ambient
PETCO2, after controlling for
ONf, remained highly significant (P < 0.002, r = 0.50), but the strength of the correlation
between hematocrit and ONf after controlling for ambient
PETCO2 was reduced
(P < 0.02, r = 0.38).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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From the wide range of comparisons that have been drawn within the RESULTS section, the following main points emerge.
First, neither DA nor ST revealed any additional respiratory drive that could not be revealed through variations in oxygen tension.
Second, the respiratory stimulation that arises through the peripheral chemoreflex in the HA and CMS groups (at PETO2 = 52.5 Torr) was substantially less than that arising in the SL group when made acutely hypoxic (PETO2 = 52.5 Torr), but somewhat more than in the SL group under euoxic conditions (PETO2 = 100 Torr).
Third, the respiratory stimulation that arises through the peripheral chemoreflex is modestly less in the CMS group compared with the HA group.
Fourth, hyperoxia produced an initial reduction in
E in all subject groups, but the subsequent
stimulatory effects of hyperoxia (similar in all groups) were
sufficient to produce a "paradoxical" increase in
E with sustained hyperoxia in both the HA and CMS groups.
Fifth, measurements of AHVR are greatly affected by prior oxygenation in all subject groups.
Sixth, for the HA and CMS groups together, there was a strong correlation between PETCO2 and hematocrit, which persisted after controlling for AHVR.
The relationship of these findings to control of breathing in HA natives and patients with CMS is discussed below.
Origins of the Drive to Breathe in the HA Native
This study found no evidence of an additional drive to breathe arising from the peripheral chemoreceptors that could be silenced by infusions of DA or ST, but not by hyperoxia. The study confirmed, in these subjects, that 20 min of hyperoxia (PETO2 = 200 Torr) resulted in an increasedE compared with E in
the chronic hypoxia of their environment. This combination of factors
does not provide any immediate explanation for why HA natives at HA breathe harder and have a lower
PETCO2 than HA natives resident at
SL, who have values for PETCO2 that
are normal for SL natives at SL (16).
Hyperoxic exposures
(PETO2 = 200 Torr) were
employed in this study to ensure that the activity of the peripheral
chemoreceptors had been reduced as much as reasonably possible with
this technique. However, regulating
PETO2 at 200 Torr will almost
certainly result in a greater degree of central stimulation of
breathing by oxygen than would occur in HA natives who move to live at
SL (where PETO2 = ~100
Torr). The present study has not provided an answer to the question of
what happens to E in HA natives after 20 min of
exposure to the euoxia of SL. Under these conditions, it may be the
case that the E of HA natives would remain below
that associated with the hypoxia of their HA environment.
The present study has provided evidence to support the notion that the
respiratory drive arising from the peripheral chemoreceptors of HA
natives at their approximately ambient
PETO2
of 52.5 Torr is somewhat greater than that arising from the peripheral
chemoreceptors of SL natives at their approximately ambient
PETO2 of 100 Torr (although it
should be noted that these measurements were all made at regulated
values for PETCO2 at 2 Torr above
ambient). Thus, if the effects of central stimulation by oxygen can be
ignored, perhaps because they do not persist into the chronic state,
there does appear to be an additional degree of respiratory stimulation arising from the peripheral chemoreceptors of HA natives at HA (compared with SL natives at SL) to explain their higher
E and lower
PETCO2.
Comparison of HA Natives and Patients with CMS
This study provides statistically significant evidence of a modestly reduced chemoreflex responsiveness in patients with CMS compared with healthy natives of HA. This finding is consistent with a previous report (23) of a trend toward lower values for the ventilatory response to hypoxia in patients with CMS (5 CMS patients vs. 6 HA natives). However, in the present study, not all measures of peripheral chemoreflex responsiveness were different between the patients with CMS and the healthy HA natives (e.g., AHVR-45), a result that is in keeping with another study that failed to find any differences in this respect (10). It should also be noted that the healthy HA group of the present study was not age-matched with the CMS group (CMS patients were, on average ~6 yr older), and values for AHVR decline somewhat with age (9).Overall, we consider that our data do not support the notion that
reduced values for AHVR play a major role in the causation of CMS.
First, like Ref. 10, we found a very great
overlap in the values for AHVR from healthy HA natives and from
patients with CMS. Second, the strong correlation between hematocrit
and ambient PETCO2 (an indirect
measure of the subject's natural level of E)
persisted when any relationship between these variables and AHVR had
been controlled for. This finding would tend to suggest that the lower
natural levels of E in patients with CMS may arise
through mechanisms other than reductions in the peripheral chemoreflex
sensitivity to hypoxia.
Effect of Hyperoxia on AHVR
One of the striking results of this study was that the measured values for AHVR in all subjects increased considerably with increasing degrees of preoxygenation before the measurements being made. Such a finding has been made previously for SL natives (8), and the present study extends this to HA natives and patients with CMS. The mechanisms underlying this phenomenon remain to be elucidated. Hyperoxia by itself causes a well characterized rise inE, which is thought to arise through an
increase in PCO2 at the central chemoreceptors
brought about by a reduction in cerebral blood flow and a reduction in
the Haldane effect (2, 13). However, most data indicate
that effects of central chemoreflex stimulation do not alter peripheral
chemoreflex sensitivity over the short term (see Ref. 3).
Furthermore, Honda et al. (8) considered that the effect
of prior hyperoxia on AHVR persisted for considerably longer than was
compatible with such a mechanism. Whatever mechanism underlies the
phenomenon, the results from this study indicate that the amount of
preoxygenation is critical when measuring values for AHVR in
populations living at HA.
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ACKNOWLEDGEMENTS |
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This study was supported by the Wellcome Trust.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK (E-mail: peter.robbins{at}physiol.ox.ac.uk).
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.
First published November 27, 2002;10.1152/japplphysiol.00858.2002
Received 19 September 2002; accepted in final form 25 November 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and somatostatin (
).
Left: SL subjects; middle: HA subjects;
right: patients with CMS. A: infusions against a
background PETO2 = 200 Torr
with PETCO2 unregulated;
B: infusions against a background
PETO2 = 100 Torr with
PETCO2 regulated at 2 Torr above
ambient; C: infusions against a background
PETO2 = 52.5 Torr with
PETCO2 regulated at 2 Torr above
ambient. Solid bars indicate period of drug infusion. Data are 1-min
averages, averaged across all subjects in each group. Error bars are
±1 SE.