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1 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160; and 2 Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-11, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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These
studies were conducted to compare the effects on systemic
O2 transport of chronically vs. acutely increased Hb
O2 affinity. O2 transport during maximal
normoxic and hypoxic [inspired PO2 (PIO2) = 70 and 55 Torr,
respectively] exercise was studied in rats with Hb
O2 affinity that was increased chronically by sodium cyanate (group 1) or acutely by transfusion with blood
obtained from cyanate-treated rats (group 2). Group
3 consisted of normal rats. Hb O2 half-saturation
pressure (P50; Torr) during maximal exercise was ~26 in
groups 1 and 2 and ~46 in group 3.
In normoxia, maximal blood O2 convection
(
O2 max = cardiac output × arterial blood O2 content) was similar in all groups,
whereas in hypoxia O2 max was
significantly higher in groups 1 and 2 than in
group 3. Tissue O2 extraction (arteriovenous
O2 content/arterial O2 content) was lowest in
group 1, intermediate in group 2, and highest in
group 3 (P < 0.05) at all exercise PIO2 values. In
normoxia, maximal O2 utilization
(
O2 max) paralleled O2
extraction ratio and was lowest in group 1, intermediate in
group 2, and highest in group 3 (P < 0.05). In hypoxia, the lower O2
extraction ratio values of groups 1 and 2 were
offset by their higher O2 max;
accordingly, their differences in
O2 max from group 3 were
attenuated or reversed. Tissue O2 transfer capacity
(O2 max/mixed venous
PO2) was lowest in group 1 and
comparable in groups 2 and 3. We conclude that lowering Hb P50 has opposing effects on
O2 max and O2 extraction
ratio, with the relative magnitude of these changes, which varies with
PIO2, determining
O2 max. Although the lower
O2 extraction ratio of groups 2 vs. 3 suggests a decrease in tissue PO2 diffusion
gradient secondary to the low P50, the lower O2
extraction ratio of groups 1 vs. 2 suggests
additional negative effects of sodium cyanate and/or chronically low Hb
P50 on tissue O2 transfer.
hemoglobin oxygen dissociation curve; leftward oxygen dissociation curve shift; chronic sodium cyanate administration; convective blood oxygen delivery; tissue oxygen extraction; tissue oxygen transfer capacity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CHANGES IN THE OXYGEN
AFFINITY of hemoglobin (Hb) tend to influence the uptake of
O2 (O2) by the blood in the
lungs in one direction and its release in the tissues in the opposite
direction. Because the magnitude of these effects varies at different
levels of inspired PO2
(PIO2), the net effect of a change in the
O2 affinity of Hb on systemic O2 transport is
difficult to predict and is still the subject of controversy
(2, 11, 14, 20,
22, 24, 31). We recently showed
(17) that increasing the O2 affinity of Hb in
rats [leftward shift of the O2 dissociation curve (ODC);
decrease in Hb O2 half-saturation pressure
(P50)] by chronic administration of sodium cyanate
resulted in a decrease in maximal O2 utilization
(O2 max) during normoxic treadmill exercise. During hypoxic exercise, however, the magnitude of the difference in O2 max between
cyanate-treated rats and untreated controls decreased; at the lowest
PO2 values during exercise,
O2 max was slightly higher in the
cyanate-treated rats (17). These changes in
O2 max were the net result of two
opposing factors: an increase in the rate of the maximal convective
delivery of O2 to the tissues
[O2 max, the product of
maximal cardiac output (
max) times the arterial
blood O2 concentration
(CaO2)] on one hand, and, on the
other, a decrease in the O2 extraction by the tissues, as
represented by the O2 extraction ratio (the ratio of the
arteriovenous O2 content difference to the
CaO2). In normoxic exercise, the leftward ODC shift
increased convective O2 delivery only modestly, whereas
tissue O2 extraction decreased substantially. Accordingly,
O2 max was lower in the cyanate-treated
rats. At lower PO2 values during
exercise, the effect of the ODC shift on convective
O2 delivery increased, whereas that on O2
extraction remained relatively constant, thus minimizing or even
reversing the overall negative effect on
O2 max (17).
The increase in the rate of O2 delivery brought about by
cyanate was exclusively due to an increase in CaO2
because was not modified by sodium cyanate administration. The
reason for the decrease in O2 extraction, however, is less
clear. It is likely that the leftward ODC shift tends to limit the
diffusion of O2 from the tissue capillary to the cell due
to the reduced capillary PO2 that results from
the shift. It is not clear, however, whether other mechanisms
contribute to the decrease in tissue O2 extraction in the
animals chronically treated with sodium cyanate. The observed decrease
in the respiratory capacity of mitochondria isolated from livers of
mice treated with sodium cyanate (21) suggests that, at
least in some tissues, cyanate may interfere with cellular O2. Alternatively, chronic cyanate
administration results in "hypoxia-like" effects (28),
such as polycythemia and pulmonary hypertension. These effects are
likely due to the reduced tissue PO2 secondary
to the low Hb P50; exposure to prolonged hypoxia could
result in changes that affect O2 extraction by the tissues.
The purpose of the present experiments was to extend our observations of the effect of a decrease in Hb P50 on O2 transport and maximal exercise capacity. Specifically, we investigated whether acutely elevating the O2 affinity of Hb, by exchanging the blood from untreated animals with blood with low-Hb P50, would have the same effect on O2 transport as that produced by chronic ingestion of sodium cyanate. The hypothesis tested was that, if the changes in O2 transport produced by cyanate administration in our previous experiments were due solely to the increase in O2 affinity of Hb and not to other effects, the results of acute and chronic leftward shifts of the ODC should be the same.
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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 and a nontreated group. Cyanate irreversibly carbamylates the amino terminus of valine and results in an increase in the O2 affinity of Hb (1). Sodium cyanate administration was discontinued at 3 wk; 7-10 days later, sodium cyanate-treated and nontreated animals were anesthetized with pentobarbital sodium (40 mg/kg ip). A PE-50 catheter was then placed in the left carotid artery, and a PE-10 catheter was placed 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 the day after the experiment. The catheters were tunneled subcutaneously, exteriorized at the back of the neck, cut at a length of 2 inches, and flame-sealed. During the experiments, the animals exercised maximally on a treadmill 24 h after surgery.
Experimental design. On the day of the experiment, the animals treated with sodium cyanate (group 1) underwent an exchange transfusion in which 6-8 ml of blood withdrawn from the animals were exchanged for an equal volume of plasma obtained from donor rats. This was done to lower blood Hb concentration ([Hb]), which is elevated by cyanate treatment (17, 28), to a normal value of ~15 g/dl blood. The isovolumic exchange transfusion was carried out with the use of a technique described before (6) in which infusion through the venous catheter and withdrawal from the arterial catheter were carried out simultaneously, 1 ml at a time. The nontreated animals were randomly assigned to either of two groups: group 2 or group 3. Group 2 animals underwent an isovolumic blood-exchange transfusion using blood obtained from rats that had received 0.2% sodium cyanate in drinking water for 3 wk; blood for the transfusion was obtained 7-10 days after sodium cyanate administration to the donors was discontinued. Group 3 served as controls and consisted of untreated rats that underwent an isovolumic exchange transfusion using blood with normal Hb P50 obtained from untreated littermates. In all cases, blood was obtained under pentobarbital anesthesia; ~12-14 ml of blood were withdrawn from each donor, after which the animal was euthanized with an anesthetic overdose. Exchange transfusion was carried out within 30 min of blood withdrawal from the donor. Approximately 20 ml of blood were exchange-transfused in each animal from groups 2 and 3.
One hour after the transfusion was finished, the animals exercised according to the protocol described below. Each experimental group was subdivided into three subgroups of six to seven animals each, which exercised at PIO2 values of 140, 70, or 55 Torr. Each rat exercised only once. The effectiveness of the exchange transfusion with carbamylated blood in reducing Hb P50 of the circulating blood of the recipient was established in preliminary experiments. The mixing technique (8) was used to measure Hb P50 in whole blood at pH 7.40, PCO2 of 40 Torr, and temperature of 37°C. In four rats treated with sodium cyanate as in group 1, P50 was 21.7 ± 0.9 Torr; this value was not significantly different from that of 22.4 ± 0.7 Torr obtained in the blood of four rats that had undergone exchange transfusion with 22 ± 1.2 ml of blood obtained from cyanate-treated rats (as in group 2). This represents a substantial decrease from the normal value of standard Hb P50 of untreated rats, which is ~34 Torr (8).Exercise protocol.
After measurement of rectal temperature, the animals were placed on a
treadmill enclosed in an airtight Lucite chamber adapted for the
determination of O2 and CO2
production (CO2) using the open-circuit
method (8). The catheters were connected, through sampling
ports located on the top of the box enclosing the treadmill, to
pressure transducers. After 30 min on the treadmill, arterial and mixed
venous blood samples were obtained via stopcocks, the blood was
replaced with homologous fresh blood from the same group, and the
treadmill was set at a speed of 10 m/min. This speed was maintained for
2-3 min, after which the treadmill was set at an angle of 10°
and the speed increased by 4 m/min every 90-120 s, until
O2 max was reached.
O2 max was defined as the
O2 for which an increase in work rate
resulted in no further increase (±5%) in
O2. If a plateau in
O2 max was not observed at the highest
two workloads, the animal was discarded. Approximately 80% of all
rats achieved O2 max, as defined here.
Arterial and mixed venous blood samples were obtained during the last
45-60 s of exercise, while O2 and
CO2 values remained steady. 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.
The box enclosing the treadmill was airtight except for the inflow and
outflow ports, which are independent of one another. 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 liters
ATPS/min using a Cameron Instruments precision gas flow
mixer. Inflowing and outflowing O2 concentrations and
outflowing CO2 concentration (inflowing gas was
CO2 free) were measured continuously and simultaneously
with an Applied Electrochemistry O2 analyzer and a Columbus
Instruments CO2 analyzer, respectively. The O2 and CO2 analyzers were calibrated with gas mixtures
measured with a precision of ±0.005%. Depending on the exercise
PIO2, the O2 concentration of
the calibrating gas mixtures was either 10 or 20%. The CO2
concentration of the calibrating gas was 0.20%. The O2 and
CO2 concentration differences between inflowing and
outflowing gases ranged from ~0.10 to 0.20% during maximal exercise.
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 inflowing
and outflowing O2 concentration difference, the outflowing
CO2 concentration, and the outflowing gas flow (expressed
in ml STPD · min
1 · kg1).
O2) were calculated from
[Hb], PO2, and oxyhemoglobin saturation using
an Hb-O2 binding factor of 1.34 ml STPD/g and
an O2 solubility coefficient of 0.003 ml · Torr1 · dl1. (ml
· min1 · kg1) was calculated as
the ratio of O2 to
CaO2-CO2.
The rate of convective blood O2 transport
(O2; ml · min1 · kg1) was calculated as the
product of times CaO2. The O2
extraction ratio was calculated as
CaO2-CO2/CaO2.
The data are expressed as means ± SE. Comparisons were made among
groups 1, 2, and 3 at a given
PIO2. Statistical analysis was
carried out using a one-way ANOVA. Significance was established with
the t-test, using the Bonferroni correction for multiple comparisons. A P value of <0.05 indicated a significant difference.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1 shows the average arterial
and mixed venous blood values of O2 saturation of Hb
observed during maximal exercise, plotted as a function of the
corresponding average PO2 values. It is clear
that chronic administration of sodium cyanate (group 1) and
transfusion of carbamylated blood into normal rats (group 2)
were effective in substantially increasing the O2 affinity of Hb above that of the control (group 3). Furthermore,
there does not appear to be a systematic difference in Hb
O2 affinity between the animals of groups 1 and
2. In Fig. 1, the ODCs (represented by the solid lines) have
P50 values of 26.2 Torr for groups 1 and
2 and 45.7 Torr for group 3. These values reflect
the low blood pH and high temperature of maximal exercise. Table
1 shows that exercise induced similar
changes in acid-base balance and temperature in groups 1 and
2, indicating that the effects of these factors on the
O2 affinity of Hb were equivalent in both groups.
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Table 2 summarizes the O2
transport variables observed during maximal exercise at
PIO2 values of ~140, 70, and 55 Torr. Both alveolar ventilation normalized for
O2 and partial pressure of
O2 in alveolar air
(PAO2) were similar in
the three groups at each PIO2 level;
however, PaO2 was lower and the alveolar-to-arterial PO2 gradient (A-aPO2)
was higher in both groups 1 and 2 compared with
that in control group 3. In all cases, the
A-aPO2 tended to decrease as
PIO2 decreased.
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O2 max during normoxic exercise was
lowest in group 1, intermediate in group 2, and
highest in group 3. The differences among groups were
significant in all cases. As exercise PIO2
decreased, the differences in O2 max
between groups became less marked: no differences were observed among
groups at PIO2 of 70 Torr, whereas
O2 max of group 1 was higher
than group 3 at PIO2 of 55 Torr (Table 2 and Fig. 2). No differences
in CaO2 among groups were observed in normoxia,
whereas CaO2 was significantly higher in groups
1 and 2 than in group 3 at both levels of
hypoxia (Table 2). Because maximal was not influenced by any of
the experimental interventions (Table 3),
the changes in CaO2 were translated into proportionate
changes in O2 max (Table 2 and Fig. 2).
The effect of the leftward ODC shift on O2 extraction by
the tissues was apparent at all PIO2
values: O2 extraction ratio was highest in group
3, intermediate in group 2, and lowest in group
1 (Table 2). The differences between groups were significant at
all PIO2 levels.
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Table 3 shows hemodynamic variables for the three groups. The major effect is shown in Pap: groups 1 and 2 both show pulmonary hypertension during normoxic exercise; as PIO2 decreased, the difference between the experimental groups and group 3 decreased, with no significant difference observed between the three groups at PIO2 of 55 Torr.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental design. The design of the present study allowed us to separate the effects of an acute leftward shift in the ODC from possible additional effects of chronic cyanate administration. Similar exercise Hb P50 values (Fig. 1) were obtained by either chronic administration of sodium cyanate (group 1) or by transfusion of blood containing carbamylated Hb to normal recipients (group 2). Because exercise was accompanied by similar changes in acid-base balance and temperature in both groups 1 and 2 at all PIO2 values (Table 1), it can be concluded that the extent to which these factors modified Hb P50 was equivalent in both groups and that both cyanate administration and blood transfusion resulted in equivalent changes in Hb O2 affinity. This is supported by the in vitro measurements (see METHODS), which showed no significant difference in whole blood standard P50 between cyanate-treated rats and rats transfused with carbamylated blood. The agent utilized to lower Hb P50 was the same in both groups 1 and 2, thus ensuring that the same conformational changes occurred in the Hb molecule in both cases. Treatment with sodium cyanate was discontinued 7-10 days before the experiments in the animals of group 1 as well as in the blood donors of group 2 to ensure elimination of sodium cyanate (1). The influence of possible nonspecific effects of the exchange transfusion was ruled out because all groups underwent transfusion. In addition, group 1 underwent plasma, rather than whole blood, exchange transfusion, which helped eliminate the confounding effect of elevated [Hb] that results from chronic sodium cyanate treatment (15, 17, 28). Finally, care was taken to avoid changes in blood volume during the exchange transfusions. Given these design features, differences in O2 transport variables between groups 2 and 3 can be explained solely on the basis of the changes in O2 affinity of Hb, whereas differences between groups 1 and 2 reflect additional effects of chronic cyanate treatment and/or chronic elevation of O2 affinity of Hb.
Systemic O2 transport and
O2 max.
The central observation of the present studies is that producing an
equivalent decrease in Hb P50 by either transfusion of blood with carbamylated Hb or by chronic administration of sodium cyanate had similar directional effects on the O2 transport
system (Table 2): in both cases, the changes in
O2 max were offset by those in tissue
O2 extraction, with the resulting
O2 max depending on the relative
magnitude of these opposing influences (Fig. 2 and Table 2). During
normoxic exercise, the negative effect of lowering Hb P50
on O2 max was relatively large because
the reduction in O2 extraction was not opposed by an
increase in O2 max (Table 2, Fig. 2).
At lower PIO2 values, the effect on
O2 max increased relative to the
decrease in O2 extraction, and the decrease in
O2 max compared with control was
attenuated or even reversed (Table 2, Fig. 2). The observation of a
dissociation between O2 max and the rate at which O2 is delivered to the tissues supports
previous observations in isolated skeletal muscles (11,
20) and intact animals (17), as well as
theoretical analysis of the O2 transport system
(29), which indicate that the rate of convective
O2 delivery to the tissues is not the only determinant of
O2 max.
O2 max to
changes in Hb P50 in humans. Although it would appear that
this contradicts our results, closer examination of both the present
data and the theoretical predictions shows otherwise. For
instance, Fig. 1 of Ref. 30 shows that, during normoxic exercise,
O2 max remains essentially unchanged as
standard P50 is increased from the normal value of 26.8 Torr to ~40 Torr. On the other hand, a decrease in
P50 from the normal value to ~15 Torr results in a
decrease in O2 max of ~20%. Thus,
although the effect is relatively small, i.e., almost halving
P50 results in a decrease in
O2 max of only 20%, it is not
negligible in these conditions. In the present experiments, a similar
relative percent reduction in actual P50 (from ~46 to
~26 Torr) also resulted in an ~20% decrease in
O2 max during normoxic exercise, from
87.6 to 72.4 ml · min1 · kg1
from group 3 to group 2, respectively.
Accordingly, after the species differences in standard Hb
P50 values [26 Torr in humans and 34 Torr in rats
(8)] are accounted for and because the theoretical
results (30) are presented in terms of standard P50 (i.e., P50 at pH 7.4, PCO2 = 40 Torr, and temperature = 37°C) vs. actual P50 values in this study, it is apparent
that the effects on O2 max of a
decrease in P50 observed in this study during normoxic
conditions are not substantially different from those predicted. In
addition, the theoretical model predicts that the effect on
O2 max of changing P50
decreases as exercise PIO2 decreases,
which is also consistent with our data in the present study (Table 2
and Fig. 2) and a previous study (17). Finally, the model
predicts that the net O2 max effect of
a change in P50 is the result of the relative magnitude of the opposing changes in arterial blood Hb O2 saturation on
one hand and of tissue O2 extraction on the other
(30), which is in agreement with the present results and
the previous findings (17).
A second important observation of the present experiments is that,
although the direction of the changes was the same, there were
quantitative differences between the effects of chronic cyanate administration (group 1) and those of transfusion of blood
with carbamylated Hb (group 2): although arterial blood
oxygenation levels and the rate of
O2 max were similar in both groups, the
O2 extraction ratio was slightly but significantly lower in group 1 than in group 2 at all
PIO2 values (Table 2 and Fig. 2). Insight
into the mechanisms responsible for the decrease in O2
extraction may be obtained by examining the relationship between O2 max and mixed venous
PO2 (Fig. 3).
Because most of the O2 utilization during maximal exercise
takes place in the exercising muscles (16), the
PO2 of mixed venous blood largely reflects the
PO2 of the blood draining the exercising
muscles. Under these conditions, skeletal muscle cell
PO2 is near zero (3,
19), and changes in mixed venous
PO2 during maximal exercise reflect changes in
the blood-to-cell PO2 diffusion gradient.
Within the framework of these assumptions, the relationship between
O2 max and venous
PO2 can be considered an indication of the
O2 transfer capacity of the tissues, a composite parameter
determined by all the processes involved in the flow of O2
from the tissue capillaries to the mitochondria (29). It
is apparent that the relationship between
O2 max and venous
PO2 in group 2 is similar to that of
the control group 3, suggesting that lowering Hb
P50 per se does not alter tissue O2 transfer
capacity. This being the case, the lower
O2 max observed in group 2 with respect to control group 3 in normoxia can be
interpreted as being the result of the decreased capillary-to-cell
PO2 gradient: as the leftward shift of the ODC
lowers the capillary PO2, the diffusion gradient is reduced and cannot support the O2 flux from
capillary to cell; as a consequence,
O2 max decreases. At the lower PIO2 values, the decreased O2
extraction ratio is compensated by the higher
O2 max (Table 2 and Fig. 2), and
O2 max does not change as much. The
slope of the line relating O2 max and
venous PO2 for the animals of group
1, on the other hand, is lower than that corresponding to the
other two groups, suggesting a reduction in the tissue O2
transfer capacity: for a given PO2 gradient,
the rate at which O2 is transferred to the cells is lower.
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O2, independent of its
effects on the Hb molecule. A decreased muscle oxidative capacity would
be evidenced by a lower O2 extraction ratio and lower
O2 max-to-venous
PO2 ratio. Alternatively, the lower
O2 extraction ratio could be the result of the chronically elevated Hb O2 affinity. Chronic cyanate administration
produces hypoxia-like effects such as polycythemia and elevated blood
[Hb] and pulmonary hypertension (Tables 2 and 3 and Refs 15, 17, and
28); the polycythemia is due to increased erythropoietin release
(15). These features suggest that the chronic leftward shift of the ODC results in tissue hypoxia, even in a normoxic environment. Previous data from our laboratory (17)
suggest that chronic cyanate administration has a negative effect on
tissue O2 transfer capacity that is offset by the increase
in [Hb]: lowering [Hb] of cyanate-treated rats to normal values
resulted in a further decrease in the O2 extraction ratio
during hypoxic exercise (17). Furthermore, for a
comparable venous PO2,
O2 max was lower in the cyanate-treated
rats with normal blood [Hb] than in both control rats and
cyanate-treated rats with high blood [Hb], whereas there were no
differences between the latter two groups (17). A positive
effect of [Hb] on tissue O2 transfer capacity is
supported by the decrease in skeletal muscle O2 diffusing capacity observed in exercising humans after the lowering of blood [Hb] (23) and the opposite effect seen in rats when
blood [Hb] is increased (6). In this respect, we have
observed (5) that chronic exposure to hypobaric hypoxia
does not influence O2 extraction ratio or tissue
O2 transfer capacity despite blood [Hb] levels that were
substantially higher than those observed here, further suggesting that
exposure to chronic hypoxia results in a decrease in tissue
O2 extraction that is offset by the increase in blood
[Hb]. The net effect of chronic hypoxia on tissue O2 extraction may be the result of the interaction of several opposing mechanisms. On the one hand, the increased [Hb] should tend to improve O2 transfer from capillary to cell. In addition,
chronic hypoxia results in a decrease in muscle fiber size mainly due to loss of myofibrillar proteins, without a concomitant decrease in the
size of the capillary network (12), which results in a
relative increase in capillary density. Interestingly, rats chronically
treated with sodium cyanate show similar morphological features in
skeletal muscle (13): a decrease in fiber cross-sectional area, an increase in capillary density, and no change in the
capillary-to-fiber ratio. It is generally thought that these features
should facilitate muscle O2 transfer by decreasing the
distance between capillary and fiber. However, recent studies
(9) showed that limb immobilization in dogs, which also
results in a lower skeletal muscle fiber cross-sectional area and
unchanged capillary-to-fiber ratio, fails to influence muscle
O2 diffusing capacity and actually results in a flatter O2 max/venous
PO2 relationship compared with control animals.
These latter findings suggest that the decreased capillary-to-cell distance that occurs in prolonged hypoxia is not necessarily translated into an improved muscle O2 transport.
In addition to structural changes, prolonged hypoxia could influence
the O2 max / venous
PO2 relationship by changes in muscle oxidative
capacity. Data on this subject are controversial, and it is possible
that the discrepancy may reflect differences in species and in severity
and duration of exposure to hypoxia. A loss of muscle mitochondria
(12) and a decrease in muscle oxidative capacity
(25) have been observed in both humans and rats exposed to
prolonged hypoxia. These changes should have a negative effect on
O2 transfer. On the other hand, studies in animals
indigenous to high altitude (10, 26,
27) and in sea-level animals acclimatized to simulated
altitude (4) demonstrated increased muscle oxidative
capacity and increased myoglobin concentration. It is clear that
further studies are necessary to determine the possible effect of
prolonged hypoxia on muscle O2 transfer in exercise.
Pulmonary circulation and gas exchange. Pulmonary hypertension was observed in both groups 1 and 2 during normoxic exercise. In group 1, no further increases in Pap were observed during hypoxia, suggesting a blunting of the hypoxic pulmonary vasoconstriction (Table 3). This agrees with previous observations in cyanate-treated rats (17, 28). The high Pap in group 2 in normoxia (Table 3) suggests that the ODC shift results in pulmonary vascular smooth muscle hypoxia severe enough to elicit pulmonary vasoconstriction. This was accompanied by a further increase in Pap during hypoxic exercise, suggesting that hypoxic pulmonary vasoconstriction was not blunted in this case. These differences may result from the differences between the effects of acute and chronic hypoxia in the pulmonary circulation, where hypoxic vasoconstriction and vascular remodeling play different roles in the pulmonary hypertension.
An interesting result of the present experiments is the effect of the increased O2 affinity of Hb on A-aPO2 , which was higher in both groups 1 and 2 than in group 3. In the presence of unchanged alveolar ventilation and PaO2, an increase in A-aPO2 indicates a decrease in the efficacy of pulmonary gas exchange. The fact that there was no difference in A-aPO2 values between groups 1 and 2 shows that the gas exchange defect is due to the leftward shift of the ODC and not to additional effects of chronic sodium cyanate administration. The higher A-aPO2 could be the result of ventilation-to-perfusion distribution heterogeneity, incomplete alveolocapillary PO2 equilibration, or a combination of both. Alveolocapillary PO2 equilibration could be impaired by a leftward ODC shift as a result of a combination of the lower venous PO2 and the steeper slope of the ODC. Theoretical analysis by Piiper and Scheid (18) shows that the likelihood of complete alveolocapillary PO2 equilibration is inversely related to the slope of the blood O2 absorption curve. A steeper ODC would result in smaller PO2 increments as blood O2 saturation increases along the pulmonary capillary. On the other hand, the positive correlation observed between A-aPO2 and PIO2 values (Table 1) is consistent with increased ventilation-perfusion heterogeneity; however, the reason that both acute and chronic ODC shifts result in comparable decreases in pulmonary gas exchange efficacy via ventilation-perfusion mismatch is not readily apparent. Independent of the mechanism responsible for the impaired pulmonary gas exchange, it is interesting to note that the negative effect on PaO2 offsets the increase in O2 saturation of Hb, particularly in hypoxia, thus limiting the beneficial results of the leftward ODC shift onO2 by the blood in the lungs.
In summary, the main relevance of the present results is that an acute
increase in the O2 affinity of Hb, isolated from any other
factors, has a definite effect on systemic O2 transport during exercise. This effect, which is relatively large in normoxic and
decreases substantially in hypoxic conditions, can be reasonably predicted from the extent of the change in Hb P50 and the
PO2 level at which exercise takes place. Our
results indicate that a decrease in P50 results in
decreases in O2 max in normoxia; this
effect decreases in magnitude as PIO2
decreases and could even be reversed in severe hypoxia. The fact
that the net effect of the ODC shift is the result of a balance between
opposing mechanisms, the magnitude of which depends on the prevalent
PO2, may help reconcile the apparently
contradictory results obtained in the past. In addition, the present
data show that the decrease in tissue O2 extraction is
largest after chronic elevation of Hb O2 affinity,
suggesting a direct effect either of cyanate or of prolonged hypoxia on
tissue O2 transfer. The results of this study show that
there is no unambiguous answer to the question of whether an increase
or decrease in P50 is most beneficial for systemic O2 transport and utilization during exercise. Perhaps the
most effective conditions to maximize O2 transport are
obtained not when large overall changes in P50 are
produced, as it was done in this and other studies, but in conditions
when O2 affinity of Hb increases as blood flows through the
lungs and decreases as it flows through the tissues. These conditions,
of course, normally occur as a result of the acid-base and temperature
changes that take place at those sites during exercise.
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ACKNOWLEDGEMENTS |
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We thank Dr. Peter D. Wagner for helpful discussion of these data. The expert technical assistance of Julie Allen is gratefully acknowledged.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-39443 and by American Heart Association, Kansas Affiliate, Grant KS96-GS-66.
Address for reprint requests and other correspondence: N. C. Gonzalez, Dept. of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7401 (E-mail: ngonzale{at}kumc.edu).
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.
Received 4 October 1999; accepted in final form 14 March 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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