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1 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160-7401; and 2 Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Systemic
O2 transport during maximal
exercise at different inspired PO2
(PIO2) values was
studied in sodium cyanate-treated (CY) and nontreated (NT) rats. CY
rats exhibited increased O2
affinity of Hb (exercise O2
half-saturation pressure of Hb = 27.5 vs. 42.5 Torr), elevated blood Hb
concentration, pulmonary hypertension, blunted hypoxic pulmonary
vasoconstriction, and normal ventilatory response to exercise. Maximal
rate of convective O2 transport
was higher and tissue O2
extraction was lower in CY than in NT rats. The relative magnitude of
these opposing changes, which determined the net effect of cyanate on
maximal O2 uptake (
O2 max), varied at
different PIO2:
O2 max
(ml · min
1 · kg1)
was lower in normoxia (72.8 ± 1.9 vs. 81.1 ± 1.2), the same at
70 Torr PIO2 (55.4 ± 1.4 vs. 54.1 ± 1.4), and higher at 55 Torr
PIO2 (48 ± 0.7 vs. 40.4 ± 1.9) in CY than in NT rats. The beneficial effect of cyanate
on O2 max at 55 Torr PIO2 disappeared when
Hb concentration was lowered to normal. It is concluded that the effect
of cyanate on O2 max depends on the relative changes in blood
O2 convection and tissue O2 extraction, which vary at
different PIO2. Although uptake of O2 by the blood in the
lungs is enhanced by cyanate, its release at the tissues is limited,
probably because of a reduction in the capillary-to-tissue
PO2 diffusion gradient secondary to
the increased O2 affinity of Hb.
hemoglobin-oxygen affinity; hemoglobin-oxygen dissociation curve; low oxygen half-saturation pressure of hemoglobin; leftward oxygen dissociation curve shift; maximal exercise capacity; systemic oxygen transport; convective oxygen delivery; capillary-to-cell oxygen diffusion; oxygen extraction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE EFFECT OF CHANGES in the O2 affinity of Hb on O2 transport and uptake is still poorly understood. A decrease in O2 affinity of Hb [rightward shift of the O2 dissociation curve of Hb (ODC) and increase in the PO2 necessary to obtain 50% O2 saturation of Hb (P50)] occurs in acclimatization to altitude, and this is thought to be advantageous for O2 transport in hypoxia, since it may facilitate O2 unloading in the tissues (1, 13). On the other hand, animals indigenous to altitude (2) show high O2 affinity of Hb (low P50 and leftward ODC shift), and rats with a leftward ODC shift showed increased survival rate to extreme hypoxia (5). Studies in quiescent or contracting isolated skeletal muscles have also shown apparently contradictory results concerning O2 transport, extraction, and utilization after changes in P50 (9, 11, 15, 17).
Despite continuing interest in the subject, relatively few data are available on the effect of changes in the O2 affinity of Hb on the mechanisms of systemic O2 transport in intact animals, particularly during maximal exercise. Experimental data on this subject are needed, because the effects of changes in O2 affinity of Hb on O2 transport during exercise are not easy to predict. In general, changes in O2 affinity of Hb are likely to have opposing effects on Hb oxygenation in the lungs and deoxygenation in the tissues. Furthermore, because the change in O2 saturation of Hb produced by a given ODC shift is smaller at PO2 above ~80 Torr and below ~20 Torr than at intermediate PO2, the magnitude of the change in O2 uptake in the lungs relative to O2 release in the tissues is likely to vary at different levels of inspired PO2 (PIO2). Finally, it is not clear how the changes in the different links of the O2 transport system secondary to ODC shifts may interact with one another in the intact organism and whether compensatory mechanisms may exist that modify the effect of these changes.
The purpose of the present studies was to determine the effect of a
leftward shift of the ODC on O2
transport and uptake during maximal exercise at various
PIO2 levels.
Maximal exercise was chosen, because maximal
O2 consumption
(O2 max) provides an
accurate measurement of the capacity of the entire transport system to
deliver and utilize O2 under a
given set of conditions; furthermore, under appropriate circumstances,
it is possible to determine the conductance of one or more of the links
that compose the O2 transport
chain. Accordingly, the effect of an experimental intervention on the
transport capacity of the entire system, as well as that of the
individual links, can be established, and the mechanism of action of
the intervention can be determined.
Our hypothesis was that a leftward shift of the ODC would result in an
increase in the maximal rate of convective
O2 delivery to the tissues and, at
the same time, result in a decrease in the extraction of
O2 by the tissues. We further
hypothesized that the relative magnitude of these two opposing changes
would determine the effect of the ODC shift on
O2 max and that this
effect would differ at different levels of
PIO2. To test this
hypothesis we used an animal, the rat, that has been used frequently in
studies of O2 transport under
different environmental conditions (3, 7, 8, 12, 21).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal model. Male Sprague-Dawley rats weighing 225-250 g were randomly assigned to two groups: a group that received 0.2% sodium cyanate in the drinking water for 3 wk (CY group) and a nontreated (NT) group. Cyanate irreversibly carbamylates the amino terminal of valine and results in an increase in the O2 affinity of Hb (4). Sodium cyanate administration was discontinued at 3 wk; 1 wk later, CY and NT animals were anesthetized using pentobarbital sodium (40 mg/kg ip); a PE-50 catheter was placed in the left carotid artery, and a PE-10 catheter was introduced into the main pulmonary artery with the help of an introducer guide catheter. Adequate positioning of the pulmonary artery catheter was determined by the blood pressure tracing and verified at autopsy 1 day later, after the experiment was concluded. The catheters were tunneled subcutaneously, exteriorized at the back of the neck, cut at a length of 2 in., and flame sealed.
Exercise protocol.
The exercise test took place 24 h after catheter placement. The animals
were weighed, their rectal temperature was measured, and they were
placed on a treadmill enclosed in an airtight Lucite chamber adapted
for the determination of O2 uptake
(O2) and CO2 production
(CO2) by the
open-circuit method. The catheters were connected, through sampling
ports located on the top of the box enclosing the treadmill, to
pressure transducers. After 30 min in the treadmill, 0.5-ml arterial
and mixed venous blood samples were obtained via stopcocks, the blood
was replaced with homologous fresh blood from the same group (CY or
NT), and the treadmill was set at a speed of 10 m/min. This speed was
maintained for 2-3 min, then the treadmill was set at an angle of
10° and the speed was increased by 4 m/min every 90-120 s
until O2 max was reached. O2 max was
defined as the O2 after
which an increase in work rate was not associated with a further
increase (±5%) in O2.
O2 and
CO2 showed steady values.
The box enclosing the treadmill was opened, and the rectal temperature
was determined within 30 s of termination of exercise.
Gas exchange and O2 transport
determinations.
Gas enters and leaves the box enclosing the treadmill through
independent in- and outflow ports.
PIO2 was adjusted to the
desired level by mixing O2 and
N2. Flow of the gas mixture entering the treadmill box was maintained constant at 20 l/min ATPS by using a Cameron Instruments
precision gas flow mixer. In- and outflowing
O2 concentrations and outflowing
CO2 concentration (inflowing gas
was CO2 free) were measured
continuously and simultaneously using an Applied Electrochemistry
O2 analyzer and a Columbus
Instruments CO2 analyzer,
respectively. Gas flow from the box was measured continuously with a
dry-gas meter. The output of the
O2 and
CO2 meters was fed into a computer
to provide determination of
O2, CO2, and the respiratory
exchange ratio every 5 s.
O2 and CO2 were calculated from
the in- and outflowing O2
concentration difference, the outflowing
CO2 concentration, and gas flow
from the box and expressed in milliliters per minute per kilogram
STPD. PIO2 was calculated from the
O2 concentration in the treadmill
gas with use of ambient barometric pressure and the appropriate (rest
or exercise) rectal temperature; "ideal" alveolar PO2
(PAO2) was calculated from
the alveolar gas equation with the assumption that arterial
PCO2
(PaCO2) is equal to
PACO2. Alveolar ventilation
(A)
was calculated as the ratio of
CO2 to
PaCO2 and expressed in milliliters per
minute per kilogram STPD.
O2)
were calculated from [Hb],
PO2, and
O2 saturation by using an
Hb-O2 binding factor of 1.34 ml/g
STPD and an
O2 solubility coefficient of 0.003 ml · Torr1 · dl1.
Cardiac output (
,
ml · min1 · kg1)
was calculated as
O2/(CaO2 
).
The rate of convective O2
transport
(
O2,
ml · min1 · kg1)
was calculated as × CaO2. The
O2 extraction ratio was calculated
as (CaO2 O2)/CaO2.
Experimental design.
Nine groups of animals were studied, with 9-12 animals each. Three
groups of CY (CY1) and three groups of NT animals were exercised at
~55, 70, and 140 Torr PIO2
each. Because sodium cyanate treatment resulted in elevated blood
[Hb] (see RESULTS and
Table 1), three additional groups of CY
rats (CY2) were included in which blood [Hb] was reduced to
the normal value by isovolumic exchange transfusion of plasma obtained
from donor rats. The transfusion was carried out immediately before the
exercise run.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although the mean body weight tended to be smaller in CY1 and CY2 than
in NT rats, the difference did not reach statistical significance
(Table 1). Administration of sodium cyanate resulted in a marked
leftward shift of the ODC, as demonstrated in Fig. 1, which shows the arterial
(SaO2) and mixed venous blood
O2 saturation of Hb plotted as a
function of the corresponding PO2 values observed for all groups during maximal exercise. The ODCs represented by the solid lines in Fig. 1 have
P50 values of 27.5 and 42.5 Torr
for CY and NT, respectively. These values reflect the low blood pH and
high temperature of maximal exercise.
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For any level of PIO2,
PAO2 and
A/O2
were comparable in NT and CY groups (Table 1); however, the
PAO2-arterial PO2
(PaO2) difference
[(A-a)PO2] was significantly
higher in CY rats (Fig. 2), which resulted
in significantly lower PaO2 values in CY rats than in the corresponding NT rats (Table 1). Within
the CY groups, the (A-a)PO2 was higher in CY2
than in CY1 rats at all
PIO2 levels.
In all groups the (A-a)PO2 values increased
with PIO2 (Fig. 2).
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[Hb] was significantly higher in CY1 than in NT rats (Table
1). The isovolumic exchange transfusion of plasma effectively decreased
[Hb] of CY2 to that of NT rats. For a given
PIO2, O2 saturation of Hb in arterial
blood was higher in CY than in NT groups, despite the lower
PaO2 of CY rats (Table 1). No
significant differences in SaO2 were
observed between CY1 and CY2 rats, except during normoxic exercise,
when SaO2 was slightly higher in CY2 rats (Table 1).
CaO2
was significantly higher in CY1 than in NT rats at all levels of
PIO2 (Table 1).
CaO2 of CY2 rats was not significantly different from that of NT rats in normoxic exercise, and values were intermediate between NT and CY1 rats at the
lower PIO2
levels (Table 1). Venous O2
saturation of Hb and
O2
were higher in the CY groups than in the corresponding NT groups at all
PIO2 values (Table 1). In
addition, at 70 and 55 Torr
PIO2,
O2 saturation in mixed venous blood and
O2
were significantly higher in CY1 than in CY2 rats (Table 1).
All groups showed the typical acid-base features of maximal exercise
observed in this model: relatively low plasma pH, hypocapnia, and low
plasma HCO3 concentration (7, 8). During normoxic exercise, the NT group showed plasma pH 7.36 ± 0.03, PaCO2 24.3 ± 0.6 Torr, and
plasma HCO3 13.6 ± 1.3 mM.
Although there was a tendency for lower pH values in CY1 and CY2 than
in NT rats, this never reached statistical significance. In hypoxic
exercise, PaCO2 of NT groups was lower (20.3 ± 0.4 and 19.9 ± 1.2 Torr at 70 and 55 Torr
PIO2, respectively)
than in normoxia, reflecting the hypoxic hyperventilation; there was no
difference between these and the corresponding
PaCO2 values of the CY groups.
The effect of cyanate administration on
O2 max varied depending
on the PIO2 as well as the
[Hb]: in normoxic exercise O2 max was highest in
NT, intermediate in CY1, and lowest in CY2 rats (Table
2); at 70 Torr
PIO2, there was no
difference in O2 max
between NT and CY1 rats, whereas CY2 rats showed the lowest
O2 max (Table 2). At 55 Torr PIO2,
O2 max was highest in
CY1 rats, with no significant difference between NT and CY2 rats. The
rate of convective O2 delivery,
O2 max, was higher in CY1 animals than in the other two groups at all PIO2 levels. In normoxia,
there was no difference in O2 max
between NT and CY2 rats, whereas in hypoxia
O2 max was higher in CY2 than in NT rats (Table 2). In all cases, the O2 extraction ratio was
significantly higher in the NT than in the corresponding CY groups. In
addition, the O2 extraction ratio was higher in CY2 than CY1 rats at 70 Torr
PIO2. In the NT groups the
O2 extraction ratio tended to
increase with the severity of hypoxia, with the difference between 140 and 55 Torr PIO2 reaching
statistical significance. This progressive tendency for an increase in
the O2 extraction ratio as
PIO2 decreased was not observed in the CY groups.
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There were no significant effects of cyanate administration on
, heart rate, or mean systemic arterial pressure
(Table 2). In general, systemic arterial pressure and vascular
resistance tended to decrease as the severity of hypoxia increased, but
the changes were comparable in all three groups. CY1 and CY2 rats showed pulmonary hypertension in normoxia; however, pulmonary arterial
pressure did not increase further with exposure to hypoxia, as it did
in the NT group (Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Sodium cyanate, as administered in the present study, substantially
increased the O2 affinity of Hb,
as evidenced by the leftward shift of the ODC, which persisted under
conditions of maximal exercise (Fig. 1). The major observation of the
present studies was that the leftward ODC shift resulted in an increase
in the rate of maximal convective
O2 delivery to the tissues; this
effect was potentiated in the CY1 groups by the elevated
[Hb] but was still evident in hypoxic exercise in CY2 rats,
where [Hb] was normal. The effect of the elevated
O2 max,
on the other hand, was offset by a decrease in the
O2 extraction ratio, such that the
resulting O2 max
depended on the relative magnitude of these two opposing changes,
which, in turn, varied with the prevailing PIO2.
Limitations of the experimental model. Sodium cyanate administration affected the O2 transport system at several levels: the pulmonary gas exchange, the rate of convective O2 transport by blood, and the O2 extraction by the tissues. These effects can largely be explained on the basis of the leftward shift of the ODC.
The possible role of cyanate effects not due to the leftward ODC shift is likely to be minor. In the present experiments the CY rats gained less weight than their littermates during the 3 wk of cyanate administration; however, during the following week their weight gain exceeded that of the NT group, such that by the time the experiments were performed there were no significant weight differences between NT and CY rats (Table 1). The rapid elimination of cyanate from the body (4) suggests that cyanate levels would be negligible 1 wk after cessation of cyanate treatment. Essentially no effects other than those secondary to Hb carbamylation have been detected in several species (4). On the other hand, a decrease in respiratory capacity of isolated liver mitochondria was demonstrated in mice treated with a higher sodium cyanate concentration than that used here (16). Whether this effect is localized to the liver or extends to other tissues such as skeletal muscle is not clear; in the same study, no effects of cyanate on resting whole bodyO2 were observed.
Ventilation and pulmonary gas exchange.
There was no difference in
A/ O2
between NT and the corresponding CY groups (Table 1), indicating that
the ventilatory response to exercise is not influenced by cyanate
administration at any of the
PIO2 values studied.
Previous studies have shown that cyanate does not modify the
ventilatory response to hypoxia at rest (3). The present data extend
these findings to the exercise condition and indicate that neither the
ventilatory response to exercise nor the ventilatory response to
hypoxia in conditions of maximal exercise is affected by cyanate.
A/c)
mismatch. The presence of pulmonary hypertension in the CY animals
would support a
A/c
mismatch as responsible for the elevated
(A-a)PO2, since the vascular remodeling that
accompanies prolonged pulmonary hypertension could modify pulmonary
blood flow distribution and lead to increased
A/c heterogeneity. On the other hand, previous studies from our laboratory showed that rats with pulmonary hypertension due to chronic
environmental hypoxia do not present a larger
(A-a)PO2 than control animals exercising in
hypoxic or normoxic conditions (7, 8). It is possible that the low
P50 as well as the presence of
low
A/c units may contribute to the low
PaO2 of the CY rats: computer models of
gas exchange indicate that a leftward shift of the ODC will
exaggerate the effect on (A-a)PO2 produced
by a low
A/c distribution (20). Additionally, the larger
(A-a)PO2 of CY2 than of CY1 rats may
result in part from diffusion limitation, since pulmonary diffusing
capacity is influenced by [Hb], which was lower in CY2
rats. Regardless of its mechanism, the decrease in
PaO2 tends to offset the beneficial
effect of the leftward shift of the ODC on the oxygenation of Hb in
the lungs.
Circulatory convective O2 transport. Cyanate administration resulted in an increase in CaO2 through an increase in [Hb] and in O2 saturation of Hb. The relative contribution of these two factors depended on the PIO2: during normoxia, CaO2 increased largely as a result of the elevated [Hb]; as PIO2 decreased, the contribution of the increased SaO2 to the higher blood O2 content of the CY rats became more important. Elevated [Hb] in normoxic environments is a characteristic of cyanate treatment (19) and is associated with elevated serum erythropoietin levels (12). This feature, as well as the pulmonary hypertension and the blunted hypoxic pulmonary hypertensive response observed by us during maximal exercise (Table 2) and by others in resting conditions (19), is characteristic of chronic cyanate administration. These "hypoxia-like" effects (19) are probably the result of the leftward shift of the ODC, which results in lower PO2 values needed to unload O2 in the tissues.
Maximal
(max) of the
CY groups did not differ significantly from that of their NT
counterparts (Table 2). This suggests that the decrease in
O2 extraction associated with the
leftward shift of the ODC did not influence myocardial oxygenation to
an extent that could result in a deterioration of myocardial
performance that would be evidenced, in turn, by a decrease in
max. Previous studies in resting conditions showed that cyanate treatment did not
modify , coronary blood flow, or flow to various
organs of rats exposed to
PIO2 values
comparable to those of the present study (21). Because
max was not
affected, the changes in
CaO2
produced by cyanate administration were translated into proportionate
changes in the maximal rate of convective
O2 delivery to the tissues.
O2 max.
The effect of cyanate on
O2 max depended on the
PIO2 and, for any
PIO2 level, on the
[Hb]. Cyanate treatment decreased
O2 max in normoxia; the
magnitude of this decrease was reduced as
PIO2 was
lowered. Eventually the effect of cyanate on
O2 max was reversed,
with O2 max of CY1 rats being higher than that in NT rats at the lowest
PIO2. When the confounding
effect of the elevated [Hb] was eliminated, O2 max was lower at all
PIO2 values in the CY rats, with the difference between NT and CY2 rats decreasing as
PIO2 was reduced (Table 2).
O2 max at various
PIO2 and [Hb]
values can be explained if the relationship between
O2 max and
O2 max
is considered (Fig. 3).
O2 max/O2 max
is the average O2 extraction
ratio, which is represented by the slope of the solid lines fitting the
NT and CY groups. In the CY and NT groups, changes in
O2 max
were accompanied by proportionate changes in
O2 max; however, as a
result of the reduced O2
extraction of the CY groups (Table 2),
O2 max was lower in CY
than in NT rats at comparable levels of
O2 max.
Accordingly, O2 max of
the CY groups was ultimately determined by the balance between the
opposing changes in
O2 max
and in the O2 extraction by the tissues. The relative magnitude of these changes varied according to
the prevailing
PIO2 and,
for a given PIO2, on the
[Hb], with the negative effect of cyanate on
O2 max being moderated
as PIO2 decreased and
[Hb] increased. Because the negative effect of the leftward
ODC shift on O2 max is
reduced as PIO2 decreases,
it is conceivable that the increase in
O2 max
may eventually outweigh the decrease in
O2 extraction when extremely low
PO2 values are reached and that a beneficial effect of a leftward ODC shift may occur in these
conditions. This could explain the higher survival rate of CY rats
exposed to a barometric pressure of 223 Torr, the equivalent of an
altitude of >9,000 m (5). Nevertheless, our results clearly show that if [Hb] is maintained constant, a leftward shift of the ODC
has a negative impact on
O2 max over a wide
range of PIO2 values.
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O2 max,
decreases as PIO2 decreases.
This is in general agreement with the directional changes observed in
the present experiments; however, the predicted sensitivity of
O2 max to changes in
P50 was very low, with
O2 max at the various
PIO2 values changing <5%
over a fairly wide range of P50
values. Part of the discrepancy between the present data and the
theoretical predictions appears to be due to the difference in the
changes in O2 extraction as a
function of PIO2: in the
present experiments the O2 extraction ratio remained relatively constant, for a given
P50 value, at the three different
PIO2 values; in the model predictions, however, O2
extraction decreased as PIO2 decreased. This behavior would tend to limit the effect on
O2 max of a change in
P50.
A major conclusion of the present study is that the rate at which
O2 is consumed by an intact animal
during maximal exercise can be dissociated from the rate of convective
O2 delivery to the tissues (Fig. 3). Although a
dissociation of O2 max
from O2 max
has been demonstrated in isolated skeletal muscle (9, 10, 15), we have
no knowledge of such an observation in intact animals. These results
show that, as it was shown in isolated skeletal muscle,
O2 max
is not the only determinant of
O2 max in intact animals.
Tissue O2 extraction.
The low O2 extraction ratio of the
CY groups agrees with previous observations of a reduction in tissue
O2 extraction and an increase in
the rate of convective O2
transport needed to maintain "critical"
O2 during progressive hypoxia
in anesthetized, cyanate-treated dogs (24). Studies on cyanate-treated
dogs exercising submaximally also showed elevated convective delivery
of O2 in hypoxia and a reduced
O2 extraction (18). However, the
effect of cyanate on
O2 max was not
determined in those studies.
O2 max would increase.
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O2 max, a concept
that has been advanced by Wagner and colleagues (9, 10, 15, 22). If
venous PO2 is considered a reflection of the average tissue capillary PO2
and if the skeletal muscle cell PO2
during maximal exercise is assumed to be very low (6, 14), then venous
PO2 values should reflect the
PO2 diffusion gradient from capillary
to cell (9, 10, 15, 22). In the present case, mixed venous PO2
(
) is taken as representative
of muscle effluent PO2. Although this is a simplification, the contribution of nonmuscle tissues to O2 during maximal
exercise is minimal, and should still largely reflect the PO2
of working locomotory muscles. If
O2 max were in part
limited by tissue O2 diffusion, a
positive correlation between
O2 max and
should be observed.
That this is the case is shown in Fig. 5, where O2 max is
plotted as a function of for
all the experimental groups. Within the constraints of the assumptions
mentioned above, the positive relationship between O2 max and
is consistent with the
notion that tissue diffusion limitation is one of the determinants of
O2 max in intact
animals: a larger PO2 gradient
between capillary and cell is needed to effect a larger O2 transfer between those sites.
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O2 max was the result
of a balance between an increase in the rate of convective
O2 delivery and a decrease in the
O2 extraction ratio, the relative
magnitude of which depended on the
PIO2 and the
[Hb]. The decrease in
O2 extraction is consistent with a
limitation of tissue O2 diffusion
secondary to the leftward shift of the ODC, which would compromise the
PO2 diffusion gradient between
capillaries and muscle cells. The data support the notion that
O2 max of intact
animals is determined by the interaction between the rate of
O2 delivered to the tissue
capillaries and the rate of O2
diffusion from capillaries to cells.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Peter D. Wagner for helpful discussions of the data. The skillful technical assistance of Julie A. Koehler is gratefully acknowledged.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-39443 and American Heart Association, Kansas Affiliate, Grant KS-96-GS-66.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: N. C. Gonzalez, Dept. of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7401.
Received 24 July 1998; accepted in final form 3 December 1998.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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