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Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially
those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American
Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2005 by the American Physiological Society.
ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at http://www.the-aps.org/.
School of Physical and Health Education, Departments of 2Physiology and 3Obstetrics and Gynaecology, and
Division of Respirology and Critical Care, Department of Medicine, Queens University, Kingston, Ontario, Canada
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.
822
METHODS
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cycle status, female subjects identified the first day of their last
menstrual cycle and the average length of their cycle. This approach
has been validated in our laboratory by using plasma progesterone
measurements (23). The study protocol and consent form were approved by the Research Ethics Board, Faculty of Health Sciences,
Queens University, and all subjects provided written consent.
Basic physical measurements included height and body mass,
forced vital capacity (FVC), forced expired volume in 1 s (FEV1), and
peak expiratory flow (model S-301, Pneumoscan). Body mass index
(BMI) was calculated as body mass/height2 (kg/m2). Body surface
area (BSA; m2) was calculated from height and body mass measurements. All female subjects were tested in the FP (range: 213 days
from the first day of menstruation) of the menstrual cycle when
circulating estrogen and progesterone levels are low and gender
differences in endocrine status are minimized.
Modified rebreathing protocol. Volunteers abstained from aerobic
and muscular conditioning exercise as well as caffeine and alcohol on
the day of testing. Two rebreathing experiments, each separated by at
least 45 min, were completed in the morning (AM) and evening (PM)
of the same day. AM and PM trials were separated by 12 h.
A modified version of Reads (24) rebreathing procedure that
includes prior hyperventilation and maintenance of a constant (i.e.,
isooxia) end-tidal O2 tension (PETO2) was used to evaluate central and
peripheral chemoreflex control characteristics (9). During each trial,
subjects breathed room air for 5 min, using a slow and deliberate
breathing pattern to avoid the short-term potentiation effect described
by Folgering and Durlinger (10). Prior hyperventilation lowered the
body stores of CO2 below 25 Torr, thereby allowing the VRT to be
identified as the partial pressure of end-tidal CO2 (PETCO2) increased
from hypo- to hypercapnia. Furthermore, prior hyperventilation permits measurement of the ventilatory response below this threshold,
independent of the ventilatory chemoreflexes (i.e., basal), estimating
behavioral drives (29). After hyperventilation, subjects were switched
from room air to a rebreathing bag containing a normocapnic (42
Torr) hypoxic or hyperoxic gas mixture. Rebreathing began with three
deep breaths, producing rapid equilibration of the PCO2 in the bag,
lungs, and arterial blood to that of the mixed venous blood. The
equilibration was verified by a plateau in PETCO2 and was a prerequisite for continuing the test. On equilibration, subjects were asked to
breathe as they felt the need.
During rebreathing, PETCO2 increased while isooxia was maintained, under computer control, at a constant hyperoxic (150 Torr) or
hypoxic (50 Torr) level. In its hyperoxic form, the modified rebreathing procedure measures central chemoreflex sensitivity equivalent to
that measured using Reads original technique (19). Continuous measures of arterial blood O2 saturation (SaO2) (model OXI, Radiometer,
Copenhagen, Denmark) and heart rate (HR) (Max-1 electrocardiograph, Marquette) were obtained throughout each test. Rebreathing
was terminated if ventilation exceeded 100 l/min, PETCO2 exceeded 60
Torr, SaO2 fell below 70%, and/or subject discomfort.
Rebreathing apparatus. During rebreathing, subjects wore nose
clips and breathed through a mouthpiece connected to one side of a
three-way T-shaped manual directional valve (11.9-ml dead space;
model 2100a, Hans Rudolph) that permitted switching from room air
to the rebreathing bag. Subjects rebreathed from a 10-liter plastic bag
connected to a volume turbine (model VMM-1100, Alpha Technologies). The volume turbine was coupled to the expiratory end of the T
valve and monitored breath-by-breath changes in minute ventilation
E), tidal volume (VT) and respiratory rate (f). A sampling tube
(V
connected to the mouthpiece side of the T valve permitted continuous
analysis of PETCO2 and PETO2 by using a respiratory mass spectrometer
(model MGA 1100, Perkin-Elmer) at a sample flow rate of 64 ml/min.
Isooxia was maintained by a flow of 100% O2 to the bag side of the
T valve. The testing system was calibrated with gases of known
concentrations and a standard 3.004-liter volume syringe (model
1922, CS-3000 AM Systems) before each rebreathing test.
823
824
RESULTS
Men (n 14)
Women (n 14)
Age, yr
Body height, cm
Body mass, kg
BMI, kg/m2
Peak flow, l/s
FVC, liters
FEV1, liters
FEV1/FVC, %
BSA, m2
25.41.12
1811.8
83.43.29
26.10.9
7.430.18
5.020.14
3.790.12
75.72.26
2.070.05
22.90.66
1641.9*
653.00*
24.10.9
4.980.27*
3.290.14*
2.790.11*
85.52.58*
1.720.04*
Values are means SE; n, no. of subjects. BMI, body mass index; FVC,
forced vital capacity; FEV1, forced expired volume in 1 s; BSA, body surface
area. *Significant between-gender difference; P 0.05.
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825
Table 2. Correlations between hyperoxic and hypoxic rebreathing responses (all subjects) and
anthropometric and spirometric variables
Basal (subthreshold)
E, l/min
V
VT, ml (BTPS)
Sensitivities to CO2
E, lmin1Torr1
V
1
VT, mlmin
Torr
Condition
Age, yr
Height, cm
Weight, kg
Hyperoxic
Hypoxic
Hyperoxic
Hypoxic
0.32
0.22
0.19
0.02
0.44*
0.36
0.44*
0.41*
0.28
0.34
0.30
0.38*
Hyperoxic
Hypoxic
Hyperoxic
Hypoxic
0.29
0.11
0.15
0.26
0.45*
0.39*
0.74
0.69
0.36
0.20
0.72
0.54
BMI, kg/m2
FVC, liters
FEV1, liters
BSA, m2
0.07
0.22
0.07
0.20
0.50*
0.47*
0.50
0.57
0.44*
0.44*
0.48
0.53
0.34
0.37
0.34
0.40*
0.15
0.01
0.37
0.17
0.44
0.37
0.75
0.64
0.45*
0.45*
0.78
0.72
0.42*
0.27
0.77
0.61
E, minute ventilation; VT, tidal volume. *Significant correlation at the P 0.05 level. Significant correlation at the P 0.01 level.
V
DISCUSSION
Table 3. Effects of gender on the ventilation, tidal volume, and breathing frequency response to CO2
under hyperoxic and hypoxic rebreathing conditions
Hyperoxia
Basal (subthreshold)
E, l/min
V
F/FVC, lmin111
V
VT, ml (BTPS)
VT/FVC, ml/l
f, breaths/min
Ventilatory recruitment
threshold for CO2
E, Torr
V
VT, Torr
f, Torr
Sensitivities to CO2
E, lmin1mmHg1
V
E/FVC, lmin1mmHg1l1
V
VT, mlmin1mmHg1
VT/FVC, mlmin1mmHg1l1
f, breathsmin1mmHg1
Hypoxia
Women
Men
Women
Men
9.91.1
3.10.4
73146
22920
14.21.1
16.32.1*
3.30.4
1,070156*
20928
16.11.9
10.51.3
3.20.4
78459
24218
13.91.3
17.72.1*
3.60.5
1,159126*
22922
16.21.9
47.50.6
46.80.8
48.81.0
49.30.5
48.40.6
50.60.5*
43.80.6
43.30.6
46.10.9
43.90.7
43.80.5
48.60.6*
2.830.27
0.900.10
102.588.80
31.562.39
1.500.25
4.350.39*
0.890.08
220.0920.51*
43.713.72*
0.950.15
4.160.50
1.270.14
157.0115.68
47.894.35
1.450.28
5.980.69*
1.220.15
335.7243.30*
66.998.25*
1.500.26
Values are means SE. f, Respiratory rate. *Significant between-gender difference, P 0.05.
J Appl Physiol VOL
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826
Table 4. Effect of gender on the central and peripheral chemoreflex contribution to the ventilatory,
tidal volume, and breathing frequency response to CO2
Central Chemoreflex
Sensitivities to CO2
Women
Men
E, lmin1mmHg1
V
E/FVC, l/min1mmHg1l1
V
VT, mlmin1mmHg1
VT/FVC, mlmin1mmHg1l1
f, breathsmin1mmHg1
2.830.27
0.900.10
102.588.80
31.562.39
1.500.25
4.350.39*
0.890.08
220.0920.51*
43.713.72*
0.950.15
Peripheral Chemoreflex
P Value
0.48
0.37
Women
Men
P Value
1.320.31
0.380.08
54.4312.06
16.333.61
0.160.24
1.640.57
0.340.12
115.6333.74
23.286.41
0.720.49
0.63
0.77
0.10
0.35
0.28
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status (20, 35, 37). In keeping with these latter results, we have
E (uncorrected) and VT (corrected and
shown that both V
uncorrected) responses to isooxic hyperoxic CO2 rebreathing
are greater in men than women. Thus our data support an effect
of gender on central chemoreflex sensitivity that may be
attributed to increased levels of circulating testosterone in men
relative to women. In this regard, laboratory animals treated
with testosterone demonstrate significant increases in central
chemoreflex responsiveness (33).
Only a few studies have examined the effect of gender on the
central chemoreflex threshold for CO2. Most studies have
shown that chemoresponsiveness, and consequently the apneic
threshold for CO2, is greater in men than women (21, 35, 37),
whereas Regensteiner et al. (26) reported that no gender
difference exists. Furthermore, Morelli and coworkers (20)
recently showed that gender has no effect on the VRT for CO2
estimated from isooxic hyperoxic CO2 rebreathing trials. Our
data confirm these latter results as estimates of the central
chemoreflex VRT for CO2 did not differ between genders.
Effect of gender on the peripheral chemoreflex. Several
studies have used the progressive isocapnic hypoxia procedure
to examine the effect of gender on peripheral chemoreflex
sensitivity (1, 13, 26, 34, 35). However, this procedure is
problematic because neither the sensitivity nor threshold of the
interaction between hypoxia and CO2 is apparent from the
E and PETO2. Moreover, the
curvilinear relation between V
PETCO2 chosen to represent isocapnia may be above or below
the VRT for CO2, resulting in an over- or underestimation of
peripheral chemoreflex sensitivity, respectively. For these reasons, we employed the modified rebreathing procedure that, in
its hypoxic form, permits measurement of the threshold and
sensitivity of the ventilatory response to CO2, mediated by the
sum of both central and peripheral chemoreflexes.
E response to CO2 during hypoxic
The sensitivity of the V
trials was significantly greater in men than women but not after
correction for FVC. However, gender differences in the slope
of the VT response persisted even after correction for FVC.
E
Because the peripheral chemoreflex contribution to the V
(corrected and uncorrected), VT (corrected and uncorrected),
and f responses were not significantly different between genders, we concluded that only central chemoreflex sensitivity is
different between men and women. White et al. (35) reported
that peripheral chemoreflex sensitivity (even after correction
for BSA) was significantly greater in men compared with
women. Similarly, Morelli et al. (20) recently demonstrated
that the ventilatory response to isooxic hypoxic CO2 rebreathing is significantly greater in men than women. However, it is
unclear whether gender had an effect on peripheral chemoreflex sensitivity, as Morelli et al. failed to determine the peripheral chemoreflex contribution to the hypoxic-hypercapnic ventilatory response. Nevertheless, our findings are consistent with
the majority of previous investigations showing that gender has
no significant effect on peripheral chemoreflex sensitivity (1,
13, 26, 27, 32, 34). Moreover, findings from our study and a
past investigation (20) demonstrate that the peripheral chemoreflex VRT for CO2 is not significantly different between
genders. Taken together, we conclude that gender has no
significant effect on the peripheral chemoreflex control of
breathing.
827
828
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This work was supported by grants from the Ontario Thoracic Society and
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