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1 Laboratoire de Physiologie et Service de Médecine du Sport and 2 Unité Mixte de Recherche 5525 du Centre National de Recherche Scientifique, Faculté de Médecine de Grenoble, Université Joseph Fourier, 38700 La Tronche, France
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Chirpaz-Oddou, M. F., A. Favre-Juvin, P. Flore, J. Eterradossi, M. Delaire, F. Grimbert, and A. Therminarias. Nitric oxide response in exhaled air during an incremental exhaustive exercise. J. Appl. Physiol. 82(4):
1311-1318, 1997.
This study examines the response of the exhaled
nitric oxide (NO) concentration (CNO) and the exhaled NO
output
(
NO)
during incremental exercise and during recovery in six sedentary women,
seven sedentary men, and eight trained men. The protocol
consisted of increasing the exercise intensity by 30 W every 3 min
until exhaustion, followed by 5 min of recovery. Minute ventilation
(E), oxygen consumption (O2), carbon dioxide
production, heart rate, CNO, and
NO
were measured continuously. The
CNO in exhaled air decreased
significantly provided that the exercise intensity exceeded 65% of the
peak O2. It reached similar
values, at exhaustion, in all three groups. The
NO increased
proportionally with exercise intensity up to exhaustion and decreased
rapidly during recovery. At exhaustion, the mean values were
significantly higher for trained men than for sedentary men and
sedentary women. During exercise,
NO
correlates well with O2,
carbon dioxide production, E, and heart
rate. For the same submaximal intensity, and thus a given
O2 and probably a similar
cardiac output,
NO appeared
to be similar in all three groups, even if the
E was different. These results suggest
that, during exercise,
NO is mainly
related to the magnitude of aerobic metabolism and that this
relationship is not affected by gender differences or by noticeable
differences in the level of physical training.
exhaled nitric oxide; recovery; gender; training
INTRODUCTION ENDOGENOUS NITRIC OXIDE (NO), is a multipurpose
messenger molecule implicated in a wide variety of biological processes
(26, 27). It is generated from the amino acid
L-arginine by several types of
NO synthase, which are usually classified as either constitutive or
inducible. The constitutive form releases low amounts of NO for short
periods in response to receptor or physical stimulation. The NO
released by this enzyme acts as a transduction molecule that underlies
several physiological responses. The inducible form generates NO in
large amounts for long periods. It is mainly induced in inflammatory
cells or in other cells such as endothelial and smooth muscle cells in
response to endotoxin and to some cytokines. These two classes of NO
synthase have been identified recently in the deep lung and upper
airways of humans (1, 3). The NO generated in the lung from the
inducible form of NO synthase may play a key role in host defense
reaction and in the pathophysiology of pulmonary diseases (25). The NO
generated from the constitutive form of NO synthase is mainly found in
pulmonary arterial and venous endothelial cells, in airway
nonadrenergic noncholinergic inhibitory neurons, and in epithelial
cells (1, 21, 22). The NO released via this type of enzymes in
pulmonary vessels is a potent vasodilatator. Moreover, in the airways,
NO generated from epithelial cells and from adventitial nerve endings
may induce bronchial and vascular smooth muscle relaxation (7, 11, 16).
Previous studies have shown that NO is continuously detected in the
exhaled air of animals and humans (8, 15, 29). Recent studies have
shown that various pathological processes linked to lung disorders,
particularly to those reflecting host defense reaction, have a
quantitative effect on the NO concentration in exhaled air
(CNO). Thus an increase in
CNO has been reported in
patients with asthma (2, 13, 20, 30), bronchiectasis (18), respiratory
tract infections (19), or hepatopulmonary syndrome (9). Although the
effect of pathological processes on
CNO is gradually being
recognized, little is known about the origin and the physiological
significance of exhaled NO output ( The aim of the present study was to obtain further information about
the NO response in exhaled air during exercise in sedentary men
(Smen) and women (Women). We,
therefore, carried out continous measurements of
CNO and
METHODS Subjects
Table 1.
Anthropometric and metabolic values
NO) in
healthy subjects under physiological conditions. Muscular exercise is a
condition that may induce considerable metabolic involvement, requiring
the regulation of both pulmonary and airway blood flow and, possibly,
the regulation of airway bronchial tone. However, a few
studies have examined the evolution of
CNO during exercise. According
to these studies, the CNO during
exercise may increase (5), remain unchanged (17, 23), or decrease (23,
24, 29, 35). Moreover, although these previous studies show that the
amount of NO appearing in the exhaled air over time increases, there is
a great variability of response between the subjects (17, 23).
NO during
incremental dynamic exercise carried out until exhaustion was reached
and during recovery. In addition, because it has been suggested that
NO during
exercise may change according to physiological conditioning (23), we compared this response with that obtained for a group of well-trained men (Tmen). In so far as
NO may be
considered as an index of NO formation within the lung, this comparison
may allow investigatation of local effects of physical conditioning on
NO formation in the lungs.
Tmen
Smen
Women
Age, yr
31 ± 2
31 ± 4
39 ± 7
Height, cm
180 ± 2
178 ± 2
164 ± 2*
Weight, kg
75.8 ± 3.5
71.0 ± 2.2
60.9 ± 4.7*
Rest
O2, l/min
0.39 ± 0.02
0.30 ± 0.03
0.25 ± 0.05*
CO2, l/min
0.31 ± 0.02
0.25 ± 0.02
0.20 ± 0.03*
RER
(
CO2/O2)
0.81 ± 0.03
0.80 ± 0.04
0.78 ± 0.02
E, l/min BTPS
12.0 ± 1.3
9.7 ± 1.5
8.3 ± 1.9
Heart rate, beats/min
77 ± 3
94 ± 7
79 ± 7
Exhaustion
O2 peak, l/min
4.39 ± 0.10
3.20 ± 0.12
2.20 ± 0.20*
CO2 peak, l/min
4.44 ± 0.10
3.29 ± 0.12
2.27 ± 0.21*
O2 peak, ml · kg
1 · min1
58.4 ± 2.2
45.1 ± 2.1
36.9 ± 2.5*
RER
(
CO2/O2)
1.01 ± 0.02
1.03 ± 0.03
1.03 ± 0.02
E, l/min BTPS
129.31 ± 5.95
98.08 ± 7.67
73.10 ± 2.85*
Heart rate, beats/min
187 ± 2
187 ± 3
176 ± 5
Maximum power, W
297 ± 5
199 ± 17
141 ± 9*
Values are means ± SE of anthropometric values and ventilatory
and cardiovascular variables obtained at rest and at exhaustion in 8 trained men (Tmen), 7 sedentary men (Smen),
and 6 sedentary women (Women).
O2, O2
consumption; CO2,
CO2 production; RER, respiratory exchange ratio;
E, minute ventilation;
O2 peak, peak
CO2 peak, peak
CO2.
*
Women
vs. Smen, P < 0.05.
Women vs.
Tmen, P < 0.05.
Smen vs.
Tmen, P < 0.005.
On the first visit to the laboratory, all subjects underwent
electrocardiographic (ECG) and basic spirometric examination. Two
subjects for whom the basic spirometric analysis showed a moderate
airway obstruction and one subject who was affected by rhinitis were
excluded from the study. The selected subjects underwent an incremental
exercise test on a cycle ergometer, with continuous measurement of the
ECG, until the heart rate (HR) approached the theoretical maximum (220 
age) and until the subjects were unable to continue, even with
encouragement. During the test, tidal volume, respiratory rate,
respiratory exchange ratio, oxygen consumption (O2), and carbon dioxide
production (CO2) were
determined continuously with the standard open-circuit method by using
an automated computerized-analysis system (Brainware, Toulon, France). Expiratory flow was measured with a pneumotachograph (Hans Rudolph) that was connected to the expiratory part of the unidirectional valve
and a differential pressure transducer. Before each test, the zirconium
oxide cell O2 (Servomex) and
infrared CO2 analyzers (Servomex)
were calibrated by using gases of known concentrations. Calibration of the pneumotachograph was carried out by using a 3-liter
syringe (Hans Rudolph). At the end of the exercise, a capillary blood
sample was taken for measurement of plasma lactate concentration. The
subjects were considered to have reached their peak
O2
(O2 peak) when three
of the four following criteria were met:
1) no further increase in
O2 with increasing
workload, 2) respiratory exchange
ratio >1, 3) HR 
90% of the
maximum predicted value, and 4)
plasma lactate value >9 mM. In addition to the determination of
O2 peak, the
advantage of this pretest was that it familiarized the subjects with
this type of exercise.
Experimental Procedure
Each subject returned to the laboratory between 7 and 15 days after completing the pretest. All Tmen were asked to avoid any physical activity the day before the test. All subjects were weighed naked, and electrodes were placed on their chests to measure HR. Then they sat on the bicycle (Monark, Varberg, Sweden) and breathed into a regular mouthpiece attached to a unidirectional T valve. Their noses were blocked with noseclips. Five minutes later, resting measurements were started, and control values were recorded for 5 min. Then the subjects began to pedal. The exercise intensity was increased by 30 W every 3 min up to the maximum power reached during the pretest. For the last step, if the subject could not complete the 3-min period, the value was considered to be representative if this last step was maintained for >1 min. The value of theO2 determined during this
step was considered as the
O2 peak. At the end
of the test, the subjects continued to pedal for 2 min at 50% of the
power reached at exhaustion and thereafter rested for 3 min while still
seated on the bicycle.
Inspired air.
Because ambient air contains a variable NO concentration,
throughout the experiments all subjects breathed synthetic air free of
NO, delivered through a Teflon tube from a pressurized gas cylinder
containing 21% O2-79%
N2 (certified, Air Liquide).
Because Teflon and polyethylene are materials that do not generate or bind NO, the purified air mixture was held beforehand in a
2,000-liter-capacity polyethylene bag. The bag was connected via a
polyethylene tube to the inspiratory side of the T valve. The internal
face of the T valve was coated with Teflon. The stability of these
materials was checked beforehand to ensure that the circuit did not
interfere with NO measurement. This stability was found to last for
>24 h. The NO and O2
concentrations were checked in the bag just before the experiment to
ensure that the inspired NO concentration was below 3 parts/billion
(ppb) and that the O2
concentration was exactly 21%.
Expired air.
The expiratory part of the T valve was connected to the standard open
circuit used during the pretest and tidal volume, respiratory rate,
respiratory exchange ratio,
O2 and
CO2 were continuously determined and their values calculated by averaging the samples every
30 s. Before each test, calibrations were carried out as during the
pretest. All measurements were corrected for ambient temperature,
barometric pressure, and water vapor and were expressed in
BTPS units for minute ventilation and
STPD for
O2 and
CO2. The
O2 measured during the last
step was considered to be
O2 peak.
For NO analysis, samples of exhaled air were drawn continuously from
the expiratory part of the T valve, at a flow rate of 400 ml/min. Water
vapor was removed upstream from the analyzer by warming the sample. The
CNO was measured by an NO/NOx
chemiluminescence analyzer (model Topaze 2020, Cosma).
The detection limit for CNO was
1 ppb. Calibration was carried out before each experiment by using a
gas mixture of 883 ppb (certified calibration, Air Liquide). Moreover,
the linearity of the measurement system for low concentrations was
checked weekly, by using 50 and then 100 ml of the same calibration NO
gas, injected into a Teflon bag filled with 3 liters of nitrogen with
the 3-liter calibration syringe (Hans Rudolph). For calibration, only
Teflon-coated tubes were used. The NO signal, which became stable after
10 s, was recorded continuously throughout the test by using a Mac Lab
data-acquisition system and was calculated by averaging the samples
every 30 s. The level of CNO was
expressed in parts per billion. The molar rate of output of
NO was
calculated by multiplying CNO
and E after correction for atmospheric
pressure and temperature. To allow comparison with previously published
values, this molar rate was expressed in nanomoles per minute and in
picomoles per minute per kilogram.
Statistical analysis.
All data are expressed as means ± SE. The variations in
CNO and
NO over the
range of exercise intensities and during each minute of recovery
underwent analysis of variance (ANOVA) for repeated measurements. When
an F-value of ANOVA was significant, the Student's t-test for paired
observation was used to determine differences between values obtained
at rest, during exercise, or during recovery. Post hoc analysis was
carried out by using the Bonferroni
t-test method of comparisons to
determine whether there were significant differences between groups.
The relationships between
NO and
cardiopulmonary variables were analyzed by standard linear regression
methods. The accepted level of significance for all statistical tests
was set at 5%.
RESULTS
Rest
O2 and
CO2 were significantly lower
in Women than in Tmen (Table 1).
Figure 1,
A and
B, illustrates the
CNO and
NO values.
Resting CNO and
NO values did
not differ significantly in the three groups. However, when all
subjects were taken into consideration, positive correlations were
found between
NO and
O2
(r = 0.63, P < 0.01),
CO2
(r = 0.62, P < 0.01), and
E (r = 0.84, P < 0.001).
NO;
B and
C) at rest and during submaximal
exercise in 8 trained men
(Tmen), 7 sedentary men
(Smen), and 6 sedentary women
(Women). Values are means ± SE. ppb, parts/billion.
Women vs.
Smen,
P < 0.05.
Exercise and Recovery
Mean values forE,
O2, and HR during submaximal
exercise are given in Fig. 2,
A, B,
and C, respectively. From 30 to 120 W,
the greatest exercise intensities completed by all subjects, O2 and
CO2, were similar in the
three groups. From 90 to 120 W, E was
higher in Women than in Smen and
Tmen. At 150 W, the greatest value
carried out by all Smen,
E, was higher in
Smen than in
Tmen. Compared with
Tmen, HR became higher for
exercise intensities >30 W for Women and >60 W for
Smen.
E;
A), oxygen consumption
(O2;
B), and heart rate
(C) at rest and during submaximal
exercise in 8 Tmen, 7 Smen, and 6 Women. Values are
means ± SE. * Women vs. Tmen,
P < 0.05. Women vs.
Smen,
P < 0.05. + Smen
vs. Tmen,
P < 0.05.
At exhaustion, as expected, the
O2 peak and the maximum
E were significantly higher in the
Tmen compared with the other groups (Table 1).
CNO
Figure 1A illustrates the changes in CNO obtained during submaximal exercise. Compared with resting values, CNO declined significantly in the three groups with increasing exercise intensity. This decrease became significant at a higher exercise intensity in Tmen than in both Smen and Women (at 180 W for Tmen and 90 W for Smen and Women, respectively). Expressed as a percentage ofO2 peak, the exercise
intensity was then 45% for Smen,
64% for Women, and 60% for Tmen.
From 30 to 120 W, the greatest exercise intensity carried by all
subjects, mean CNO for a given
exercise intensity, did not differ between groups.
Figure 3A
illustrates the CNO observed at
exhaustion and during recovery. At exhaustion, mean
CNO reached similar values in all three groups. This mean value was ~40% lower than the resting value. During recovery, CNO
increased, and 5 min after exhaustion reached values that did not
differ significantly from resting values measured before exercise.
NO
(B and
C) at rest, at peak
O2
(O2 peak), and during
recovery in 8 Tmen, 7 Smen, and 6 Women. Values are means ± SE. * Women vs.
Tmen,
P < 0.05. + Smen
vs. Tmen,
P < 0.05.
NO
NO as work
rate increased, expressed in nanomoles per minute.
NO rose
significantly in the three groups for exercise intensities >30 W. Mean values obtained at 30, 60, 90, and 120 W were similar in all three
groups.
At exhaustion (Fig. 3B), the
NO values were
significantly higher in Tmen than
in Women and in Smen. During
recovery, (Fig. 3B) compared with
values obtained at exhaustion,
NO decreased significantly after the second minute. Five minutes after exhaustion, the values remained significantly higher than resting values measured before exercise in Tmen
(P < 0.05) and Women
(P < 0.01). Mean values did not
differ significantly between the three groups.
During exercise, positive correlations were found in each subject
between NO and
O2 (Fig
4, A,
B, and
C),
E,
CO2, and HR (Table
2). At exhaustion, when all subjects were
considered, positive correlations were also found beween
NO and
O2 peak (r = 0.61, P < 0, 01) and between
NO and
E (r = 0.65, P <0.01).
NO and
O2 during an incremental
exercise in 8 Tmen
(A), 7 Smen
(B), and 6 Women
(C).
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The change in
NO during
exercise has also been reported, expressed relative to body weight
(Fig. 1C). With this mode of expression, a higher
NO was found
in Women than in Smen at 120 W,
and no significant differences in
NO between
groups were found at exhaustion (Fig.
3C).
DISCUSSION
This study demontrates that in sedentary men and women, as well as in
men who trained regularly, CNO
decreases during incremental exercise if the exercise intensity exceeds
65% of O2 peak.
NO increases
in proportion to exercise intensity up to exhaustion and then decreases
rapidly during recovery. During exercise,
NO correlates
well with parameters that increase during graded exercise such as
O2,
CO2,
E, and HR. At exhaustion, the higher the O2 peak, the higher the
NO.
For a same submaximal exercise intensity,
NO is similar,
although E differs in the three groups.
It seems that, for a given exercise intensity,
NO is not
affected by differences in gender or weight or by noticeable differences in the level of physical training.
At rest, the mean values for CNO
and NO
observed in this study are higher than those found by Persson et al.
(29) and Trolin et al. (35), lower than those of Iwamoto et al. (17) and Matsumoto et al. (24), and close to those of Bauer et al. (5) and
Maroun et al. (23). The correlation found in our study between
O2 and
NO at rest
suggests a relationship between the magnitude of the metabolism and
NO. This
observation is in agreement with that related by Iwamoto et al. (17),
who found that
NO is
relatively constant at rest if
O2 is unchanged.
According to previous studies, during exercise,
CNO may increase (5), remain
unchanged (17, 23), or decrease (23, 24, 29, 35). With the exception of
the studies carried out by Iwamoto et al. (17) and Phillips et al.
(31), the data of the above studies were obtained in subjects
exercising at only two (5, 24, 29) or three work levels (23) and at
various levels of
O2 peak. The
CNO was not measured
continuously in any of these studies. This may account for the great
fluctuation in CNO during graded
exercise that was found by Iwamoto et al. (17). Our study shows that to
obtain a significant decrease in
CNO in all subjects, exercise
intensity must exceed 65% of the
O2 peak. On the other
hand, in accordance with previous studies, we have observed an increase
in NO even for
a low exercise intensity. In our subjects this increase is proportional
to the exercise intensity up to exhaustion, and correlations have been obtained between
NO and
O2,
CO2,
E, and HR. These correlations are
consistent with those obtained between
NO and
O2 and HR by Maroun et al.
(23) in their athletic group, with HR by Bauer et al. (5), and with
these same variables, but only in some subjects, by Iwamoto et al.
(17). During exercise these four variables correlate with one another,
and it is difficult to know how they relate to
NO. However,
these data suggest that, during exercise,
NO is mainly
related to physiological mechanisms linked to the magnitude of the
aerobic energy expenditure.
In this study, for a same exercise intensity,
NO is similar
in Women and Smen and in
Tmen. These findings are not
consistent with the results of Maroun et al. (23), who reported a
higher amount of
NO in the
athletic group when compared with both an intermediate and a sedentary
group. The higher
O2 peak value and the
considerably greater degree of training carried out by their athletic
group, rowing for up to 48 h/wk, may explain this discrepancy. On the
other hand, Maroun et al., as well as Bauer et al. (5), express the
values of NO
only in relation to body weight. Using this mode of expression, we
found significantly greater
NO during
exercise in Women than in Tmen and
no significant differences in
NO between
groups, at exhaustion. Because the women weighed less than the men, the
significance of this result may be debatable. During exercise,
NO
seems to be mainly related to the magnitude of the energy
expenditure. Body weight is a factor that affects the energy expended
in many forms of exercise. However, during exercise with stationary
cycling, the weight is supported and the effect of body weight on
energy expenditure is very low.
The fact that NO was present in expired air while it is practically
absent in inspired air points to the endogenous origin of the exhaled
NO. Given the rapid fixation of NO to the blood, it is likely that the
NO detected in exhaled air is formed within the respiratory system and
that the site of production is close to the pulmonary air space. There
are several possible sources of NO production in the lung where
inducible and constitutive forms of NO synthases have been identified
(3). The NO released by the inducible form is essentially generated in
inflammatory cells or in other cells such as endothelial and smooth
muscle cells in response to endotoxin and some cytokines. The NO
generated by this enzyme may play a key role in host defense reactions
and in the pathophysiology of pulmonary diseases (25). Although such an
origin cannot be ruled out, it is unlikely to explain the increased
amounts of NO in exhaled air during exercise in healthy subjects. The
NO generated in the lung from the constitutive form of NO synthase may
be released in arterial and venous endothelial cells, nonadrenergic
noncholinergic inhibitory neurons, and human lung epithelial cells (1,
3, 21). The respective contribution of these different types of cells
to the exhaled NO output of resting subjects is not yet known.
Endogenous NO production may originate from the upper respiratory tract
and, in particular, the nasal epithelium, the lower airways and
terminal bronchioles, the alveolar capillary bed, and the endothelium
of pulmonary arteries (1, 10, 21). The noseclip used in the present
study minimized the upper respiratory contribution to the
CNO. The fact that
tracheotomized rabbits, rats, and guinea pigs excrete NO in the exhaled
air (15) and that NO may be measured in intubated patients (14)
demonstrates that NO is also derived from the lower respiratory tract.
On the basis of a comparison between excretion of
CO2 and NO, and of an increase in
NO after the
breath is held, Persson et al. (29) suggest that the major site of
formation is in, or close to, the small airways epithelium. In
addition, from the measurement of the
CNO of isolated perfused and
ventilated porcine lungs, where bronchial circulation is not
functional, Cremona et al. (10) gave convincing evidence that, despite
the high affinity of hemoglobin for NO, the pulmonary vascular
endothelium may contribute to the NO found in exhaled air. However, the
possibility for NO to be able to enter the alveolus from vascular
endothelium may be questioned. Indeed, Kobzik et al. (21) failed to
find NO synthases in the pulmonary capillary endothelium, detecting NO
synthases only in the endothelium of larger pulmonary vessels.
Alternatively, Steinhorn et al. (34) found that adventitia may be a
barrier to NO in rabbit pulmonary artery. A direct
diffusion of NO from the endothelium of large vessels toward the
airways is thus questionable.
The mechanism that causes a rise in
NO during
exercise is not clear. The close relationship observed in our data
between the NO
and variables related to the magnitude of the metabolism strongly
suggests that the origin of exhaled NO is linked to structures dependent on functions that become involved progressively as metabolism increases. Among these functions, E has
been suggested as being an important stimulus of
NO.
Persson et al. (29) found that voluntary hyperventilation at
levels of E that are achieved during
exercise elicited a similar increase in
NO. This
finding is supported by recent data (31) that show that, at rest,
isocapneic hyperventilation increases
NO, although
the response is not as important as in the study of Persson et al.
These data are in contradiction with other studies showing that
voluntarily hyperventilation without exercise causes no change in NO
excretion in exhaled air (5, 17). That E
is the only stimulus involved in the increased NO during
exercise is thus dubious. This increase may also be related to
hemodynamic alterations due to exercise. In our subjects, a correlation
was found between
NO and HR.
However, whereas HR at exhaustion was similar in all three groups,
NO was greater in Tmen than in both
Smen and Women. Like
NO, HR and
cardiac output increase in proportion to the exercise
intensity. At a given exercise intensity and
O2, cardiac output increases
to similar magnitudes in sedentary and trained subjects (4). In our
study, at a given exercise intensity, the increase in
NO is also similar in sedentary and trained subjects. Moreover, at exhaustion, a close relationship exists between maximum cardiac output
and the capacity to achieve a high level of aerobic metabolism. Similarly, we observed a correlation between
O2 peak and
NO: the higher
the O2 peak, the higher
the NO.
Finally, during recovery,
NO decreases
rapidly with the variables linked to metabolism. In the peripheral
vasculature, an increase in shear stress leads to enhanced endothelial
NO release (28). It is possible that the progressive increase in
cardiac output, and hence in pulmonary blood flow, stimulates pulmonary
endothelial cell production of NO in proportion to the exercise
intensity. However, this attractive mechanism may be involved in the
increased NO
during exercise only if the NO synthetized by endothelial cells can
find its way into the airways. As discussed above, this possibility may
be debated because of the impermeability of the pulmonary adventitia
for NO (34) and the high affinity of NO for
oxyhemoglobin. Another possibility is that the binding of NO to oxyhemoglobin is reduced in proportion to exercise intensity. Because oxyhemoglobin represents a huge sink for NO, part of the NO
produced in the lung may diffuse across the alveolocapillary membrane
to bind oxyhemoglobin. In this way, the NO exhaled at the mouth is some
function of what is produced locally within the lung and what diffuses
toward the blood accross the alveolocapillary membrane. Thus it is
possible that the increased excretion of NO in exhaled air during
exercise is secondary to a decreased efficiency of the pulmonary
capillary sink for NO or to a decrease in the pulmonary diffusing
capacity for NO.
According to its origin, endogenous NO production might function as an
important regulator of airway and pulmonary blood flow and as a
regulator of bronchomotor tone (7, 11, 16). Thus NO increases
in proportion to E. Breathing
requires both warming up and humidification of inspired air before the
air reaches the alveoli. At rest, nasal mucosa is efficient for these
purposes. During physical exercise, the nose opposes a large resistance to airflow and mouth breathing occurs. Thus in our study, the noseclip
did not alter the physiological ventilatory response during exercise.
During inspiration, heat is transferred from the walls of the
tracheobronchial airways to the air by conduction and convection. In
addition, water evaporates from the airway lining fluid to saturate
air. Both heat and water are provided to the airway epithelium by
increased blood flow and vasodilatation (33). Because NO may induce a
vasodilatation of bronchial vessels, an increase in
NO may play an
indirect role in the warming up and humidification of the inspired air.
On the other hand, NO generated by endothelial cells mediates
vasodilatation in response to physical and chemical factors (1).
Because alveolar vessels present a large endothelial surface area, it
is possible that an increased NO production may decrease pulmonary
vascular resistance and participate to the recruitment of pulmonary
capillaries during exercise. Moreover, at a concentration of 10-80
ppm, exogenous NO counterbalances hypoxic vasoconstriction (28). It is
thus possible, as suggested previously (17, 23), that an increased NO
production gradually enhances the perfusion of well-ventilated lung
areas, resulting in improvement in the ventilation-perfusion distribution and enhancement of pulmonary
O2 exchange during exercise. Furthermore, NO appears able to relax airway smooth muscles. Thus NO
donors, such as nitrates, have been used in the treatment of bronchospasm for more than a century. Moreover, at high concentrations, exogenous NO in inhaled air may act as a bronchodilator (11, 12, 16).
These observations support the concept that NO may be involved in the
control of airway reactivity and play a role in the control of
bronchial tone during exercise. Most studies that have investigated
airway function during exercise have found evidence for
bronchodilatation (6). The NO delivered during exercise may favor the
occurrence of bronchodilatation, to reduce airway resistance at high
levels of ventilation.
In summary, our results indicate that
NO increases
in proportion to exercise intensity, up to exhaustion, and rapidly
decreases during recovery. This output correlates well with parameters
that increase during graded exercise such as
O2,
CO2,
E, and HR. It appears that, for a given
submaximal exercise intensity, and thus for a given
O2, and probably for a
similar cardiac output, the
NO is similar
in Smen and Women and in
Tmen. These results suggest that,
during exercise,
NO is mainly
related to the magnitude of the aerobic metabolism and that this
relationship is not affected by differences in gender or by noticeable
differences in the level of physical training.
ACKNOWLEDGEMENTS
This research was supported by a grant from the Programme thématique régional Rhône-Alpes.
FOOTNOTES
Address for reprint requests: A. Therminarias, Laboratoire de Physiologie, Faculté de Médecine de Grenoble, Université Joseph Fourier, 38700 La Tronche, France.
Received 25 June 1996; accepted in final form 12 November 1996.
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