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1 Department of Medicine, University of California, San Diego, La Jolla, California 92093; and 2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O2 through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO2 when crocetin is given. To determine whether crocetin enhances diffusion of O2 between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O2 at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 µg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 µg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O2 and CO2. TSC had no effect on ventilation, cardiac output, O2 consumption, arterial PO2/saturation, or pulmonary O2 diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO2 output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of ~10 min. We conclude that, in this model of extensive pulmonary O2 diffusion limitation, TSC as given has no effect on O2 exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O2 is not rate limiting without TSC cannot be discerned from the present study.
diffusing capacity; ventilation-perfusion inequality; multiple inert gas elimination technique
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A SERIES OF RECENT PUBLICATIONS from the laboratory of Gainer et al. (2, 6, 8, 10, 16) have provided intriguing evidence that the carotenoid compound crocetin enhances systemic O2 transport and tissue oxygenation in a variety of circumstances. In the papain-treated rat model of emphysema (2), arterial PO2 was restored to normal after 4 wk of daily administration of crocetin at 0.5 mg ip. Similar data were obtained in normal anesthetized rabbits (10). In hemorrhaged rats, cerebral tissue PO2 measured by microelectrodes was 7.6 Torr after a single intravenous bolus of crocetin (16) compared with 3.2 Torr in untreated but hemorrhaged rats. In other hemorrhaged rats, crocetin injected into a carotid artery resulted in 100% survival, whereas control animals suffered 50% mortality (6, 8). It was proposed that the physiological basis of these remarkable effects is enhanced diffusion of O2 in plasma and in vitro evidence for such an effect was presented (6), although the physicochemical basis remains obscure (5).
Although these results in intact animals appear to show overall enhancement of O2 supply to tissues, the physiological mechanism(s) remains to be determined. The experimental approaches in these studies lack the discrimination to discern between effects of crocetin on many of the steps in the O2 transport chain from the environment to the mitochondria.
Because the proposed mechanism is enhanced diffusion of O2
through plasma, it would make sense to examine the effects of crocetin in a diffusion-limited setting. Thus, if diffusive equilibrium between
alveolar gas and pulmonary end-capillary blood exists, enhancing plasma
diffusion of O2 would not be expected to improve O2 transport. Because diffusion limitation is not thought
to play a role in the hypoxemia of emphysema, at least in humans
(1, 14, 15, 19), it
is difficult to understand the basis of improved arterial
PO2 in the emphysematous rat (2).
Perhaps crocetin stimulated ventilation or altered
ventilation-perfusion (
A/
) relationships in
some manner. Similarly, in the hemorrhaged rats (16),
tissue perfusion or its distribution, rather than diffusion, may have
been improved to explain the higher tissue PO2 values.
Because of these uncertainties, we designed a study to directly test
the hypothesis that crocetin improves arterial
PO2 through enhanced diffusion. We used doses
similar, per kilogram of body weight, to those reported in the studies
of Gainer et al. (8, 10, 16). We
chose the exercising foxhound in which to study gas exchange, because,
in hypoxia, this species becomes greatly diffusion limited in its
pulmonary gas exchange (11). This is seen even in the
intact foxhound but is more pronounced after recovery from partial lung
resection. We used the multiple inert gas elimination technique (MIGET)
(4, 20) to distinguish among the various
causes of hypoxemia: 1) diffusion limitation, 2)
A/ inequality, 3) shunt, and
4) hypoxemia from relative hypoventilation during exercise.
In summary, we were unable to show any effect of crocetin on arterial oxygenation, despite conditions of considerable alveolar-capillary O2 diffusion limitation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Five foxhounds were used in the study, which had been approved by the University of Texas Southwestern Medical Center Animal Use Committee. Two of the animals had previously undergone bilateral lobectomy, one had undergone right pneumonectomy, and the other two were sham-operated controls with normal lungs. All were males, and their average weight was 23.5 kg.
Outline of the protocol. All studies were carried out with the dogs breathing 14% O2 to magnify O2 diffusion limitation of pulmonary gas exchange. Each dog was studied twice, with 1 h separating the two experiments. After catheterization (see below), data were collected in duplicate 1) at rest, 2) during moderate exercise, and 3) during heavy exercise. For all dogs, moderate exercise consisted of running at 6 miles/h on a horizontal treadmill. Heavy exercise involved running at 8 miles/h at inclines of 0-15% depending on the capabilities of each dog. The target load for heavy exercise was to attain the highest power output sustainable for the 5 min required to reach a steady state and then to complete sampling procedures. The two executions of this protocol were purposely identical to each other in speed, incline, and duration. The first run was the control experiment, in which only the phosphate buffer used to dissolve crocetin was given; the second run was commenced <5 min after the intravenous injection of 100 µg/kg of crocetin given as the trans isomer of sodium crocetinate (TSC). Given a blood volume of 70-100 ml/kg, initial blood concentration would be 0.7-1.0 µg/ml. In three of the dogs, the disappearance of TSC from plasma was followed spectrophotometrically for ~20-30 min with use of blood samples collected during the actual experiment. TSC was kindly supplied by Dr. John Gainer (Dept. of Chemical Engineering, University of Virginia).
Dog preparation. Three catheters were placed percutaneously in each dog (with use of local anesthesia and sterile technique) immediately before the study: a carotid artery catheter was placed into a previously elevated carotid artery, a jugular venous catheter was used to infuse the saline solution of the six inert gases used in the MIGET, and a thermodilution Swan-Ganz catheter was advanced into the pulmonary artery. From these catheters, systemic and pulmonary arterial pressures were continuously monitored and blood samples were withdrawn at designated times. In addition, the pulmonary arterial catheter recorded central body temperature. All catheters were secured by a collar and led out around the back of the neck to be connected to pressure transducers and sampling ports. Vascular pressures were referenced to a fluid-filled catheter sutured to the dog's midchest along the anteroposterior diameter.
Each dog was fitted with its own previously constructed tight-fitting face mask that was connected to a Hans Rudolph nonrebreathing valve. This valve was connected on the inspired side to a meteorological balloon (200 liters) kept full with 14% O2. The expired side was connected to heated, metal mixing boxes, so that mixed expired inert and respiratory gas concentrations could be sampled as desired.Measurements.
Ventilation was measured on the expiratory side by a heated, calibrated
Hans Rudolph pneumotachograph (model 4813) and reported as
BTPS. Mixed expired O2 and CO2
concentrations were measured continuously by a mass spectrometer (model
MGA 1100, Perkin-Elmer), and O2 consumption
(O2) and CO2 production
(CO2) were calculated, averaged, and
displayed every 10 breaths in real time to monitor attainment of a
steady-state O2 during exercise.
![[O<SUB><IT>2</IT></SUB>]<IT>=1.39×</IT>[Hb]<IT>×% </IT>O<SUB><IT>2</IT></SUB> saturation<IT>/100+0.003×</IT>P<SC>o</SC><SUB><IT>2</IT></SUB>](/content/vol89/issue1/fulltext/235/img001.gif)
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O2, cardiac
output was computed as the ratio of O2
to arteriovenous [O2] difference. O2
half-saturation pressure of Hb (P50) was determined as the
value that minimized the sum of squares of the differences between
measured O2 saturation and that calculated from measured
PO2, PCO2, and pH with
use of the Kelman algorithms (12, 13) over
all 12 (6 arterial and 6 venous) samples before administration of TSC.
The same process was used to separately calculate P50 from
the 12 blood samples taken during the second exercise run after
crocetin administration.
The alveolar gas equation was used to compute the alveolar-arterial
PO2 difference (A-aPO2)
from the temperature-corrected arterial PO2 and
PCO2 values and the measured respiratory
exchange ratio.
The MIGET was utilized in the manner described previously
(4, 11). Duplicate 20-ml mixed expired
samples were collected at the same time as single 6-ml arterial blood
samples at each of the six times of data collection (rest and moderate
and heavy exercise) before and after administration of TSC. Because of
time limitations, which prevented blood sampling from the Swan-Ganz catheter, measured values of ventilation and cardiac output were used
to compute pulmonary arterial inert gas levels by mass balance from the
expired and arterial levels. From the resulting retention and excretion
ratios of the six gases (SF6, ethane, cyclopropane, enflurane, ether, and acetone), moments of the
A/ distribution were computed in the standard
manner. We used the second moment about the mean on a logarithmic scale
as the index of A/ dispersion. In addition,
arterial PO2 was predicted from the
MIGET-derived A/ distribution and compared
with the measured arterial PO2. When the former
exceeded the latter, indicating causes of hypoxemia over and above
1) A/ inequality, 2)
shunt, and 3) inadequate ventilation, a whole lung diffusing
capacity (DLO2) was
calculated from the algorithm of Hammond and Hempleman
(9). Especially in hypoxia, when the measured arterial
PO2 is less than that predicted via MIGET,
alveolar-capillary diffusion limitation is the generally accepted
explanation, although postpulmonary shunting could in theory also
account for such a difference (18). The calculation of
DLO2 explicitly assumes that,
regionally, diffusing capacity is distributed in proportion to local
blood flow. Accordingly, this estimate of
DLO2 is the lowest whole lung
value that will account for the difference between measured and
predicted values of arterial PO2. In the
context of the present study, DLO2
is a lumped parameter that per se cannot ascribe specific resistance to
diffusion to any component of the O2 transport pathway
between alveolar gas and Hb within the red blood cell. However,
comparison of values before and after TSC will reveal any change in
overall conductance for O2 across the lung independent of
A/ inequality, shunt, and ventilation.
Spectrophotometric analysis of TSC in plasma. Remaining arterial blood samples used for MIGET analysis or blood-gas measurement were centrifuged at 4,200 rpm for 10 min, and the plasma was removed and protected from light. Diluted TSC and plasma before TSC injection were also obtained, and all samples were scanned in a spectrophotometer (model DU-70, Beckman). Absorbance at 540 nm (where TSC shows no activity) and absorbance at 450 nm (where TSC shows peak activity) were measured. The value at 450 nm was corrected for the (non-TSC) signal appearing at 540 nm to yield a value reflecting the contribution of TSC to the 450-nm signal. From semilogarithmic plots of absorbance as a function of time after TSC injection, plasma half time was computed in three dogs.
Statistical analysis.
Repeated-measures ANOVA was used to assess the effects of TSC and
exercise on the principal outcome variables pertaining to gas exchange,
with P
0.05 set as the discriminating level of significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Global variables: ventilation, cardiac output,
O2, and
CO2.
Figure 1 shows the relationships
between O2 and
CO2 before and after TSC at rest
and during moderate and heavy exercise. O2 was clearly unaffected by TSC, with
values at each metabolic rate on the identity line. However,
CO2 appeared systematically reduced,
albeit to a minor degree. Although this reduction failed to reach
significance, the ratio of CO2 to
O2 (i.e., the respiratory exchange
ratio) was systematically lower after TSC by 0.1 unit (P = 0.05).
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O2, and demonstrates no effects of TSC.
Neither systemic- nor pulmonary artery-cardiac output relationships
were affected by TSC (not shown).
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O2 and show that 1) TSC had
no effect on measured or predicted values of arterial
PO2, 2) predicted
PO2 was considerably higher than measured
PO2 during moderate and heavy exercise,
3) TSC was associated with an arterial
PCO2 that was lower by 2-3 Torr
(P = 0.01), 4) there was no difference
between measured and predicted arterial PCO2
before or after TSC, 5) TSC had no effect on the measured
A-aPO2 but was associated with a slightly
reduced predicted value for A-aPO2 of 1 Torr
(P = 0.001), and 6) during exercise, but not
at rest, the measured A-aPO2 greatly exceeded
the predicted values (18 vs. 5 Torr, P < 0.001),
indicating that the great majority of the
A-aPO2 is due to diffusion limitation. Figure 3
also shows that measured arterial O2 saturation was not
affected by TSC but fell significantly with exercise.
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A/ inequality, as depicted by
log SD, the second moment of the perfusion
distribution about its mean, after treatment with TSC. This explains
the small reduction in predicted A-aPO2 of 1 Torr shown in Fig. 3. Also shown in Fig. 4 is
DLO2; TSC had no significant effect
on this variable.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Summary of major findings.
In contrast to the reports from the laboratory of Gainer et al.
(2, 6, 16), we were unable to
confirm enhancement of pulmonary O2 diffusive transport by
TSC in a highly diffusion-limited situation of hypoxic exercise. We did
note some minor differences between the control and post-TSC runs, but
these were related to 1) changes in
CO2 and CO2 transport
and 2) changes in A/ matching.
Lack of effect of TSC. The lack of effect of TSC in the present study could have several explanations. First, the diffusion-enhancement hypothesis, in vivo, may not be true. In vivo, convective motion of red blood cells in the pulmonary circulation could overcome potential diffusive resistance of the plasma, such that the potential benefit of TSC may not be realized. Second, even if TSC enhances plasma O2 movement, if that component of O2 diffusive exchange between alveolar gas and capillary blood is quantitatively minor, TSC may have no measurable effect. Thus, if crossing the alveolar-capillary membrane and/or binding to Hb in the red blood cell offer the major resistances to O2 exchange, the plasma enhancement may not accelerate the overall exchange process to any measurable degree. Third, the concentration of TSC may have been insufficient to elicit an effect. It appears that TSC disappears rapidly from the plasma (Fig. 5), but even at this rate about one-half the initial concentration should have still been present at the time of the final measurement during heavy exercise. We used doses similar, per kilogram of body weight, to those used by others (M. Singer, R. P. Stidwell, A. Nathan, and J. L. Gainer, unpublished observations). Figure 4 could be interpreted as providing tantalizing evidence in this direction, since at moderate exercise the post-TSC DLO2 is numerically greater than the pre-TSC value. Because moderate exercise was always performed sooner after TSC administration than was heavy exercise, the TSC levels must have been higher. Figures 4 and 5 do provide a rationale for repeating these studies at higher doses and, possibly, by continuous infusion to maintain plasma levels. The fourth possible reason for lack of effect of TSC is that O2 exchange at the lungs was not diffusion limited. This is regarded as extremely unlikely given that the measured A-aPO2 of ~18 Torr exceeded the predicted value at heavy exercise by ~13 Torr (Fig. 3). The only other explanation for the difference under hypoxic conditions between predicted and measured arterial PO2 would be a postpulmonary shunt through the bronchial or thebesian venous circulation, but a shunt of >15% of the cardiac output would be required to account for the 13-Torr difference. This is unreasonably high, since such shunts are generally only on the order of 1-2% at most.
Reconciliation with previous work.
The only previous reports of crocetin affecting pulmonary gas exchange
(2, 6) involve conditions of rest and
normoxia, in which alveolar-capillary diffusion limitation is generally not seen, especially in health, but even in diseases (1,
14, 15, 21). In the study by
Holloway and Gainer (10), arterial PO2 rose progressively over 3 h, whereas
cardiac output and iliac (not pulmonary arterial)
PO2 remained constant. Factors not considered by these authors, such as progressive changes in whole body
O2 or pulmonary
A/ relationships, might have contributed to
the changes in arterial PO2. In the
emphysematous rats (2), levels of ventilation and/or
cardiac output or degrees of A/ mismatch may
have differed between groups to account for differences in arterial
PO2; unfortunately, arterial
PCO2 values were not given. Thus definitive
explanations for the differences between previous studies and the
present experiment cannot be given, since in the prior work many key
variables could not be measured.
Differences in CO2 and
CO2 transport between first and second exercise bouts.
CO2 and the respiratory exchange ratio
were systematically lower after than before TSC, and these data were
mirrored by independently measured reductions in arterial and mixed
venous PCO2. Although the effects were
physiologically minor (0.1-unit reduction in respiratory exchange
ratio, 3- to 4-Torr reduction in PCO2), the
question arises as to whether this result was due to TSC. It may have
been due to persisting metabolic effects of the prior (control)
exercise run without TSC, causing a shift away from carbohydrate toward
fat as a substrate for metabolism during the second run
(7). It would be necessary to repeat the entire study with
two "control" runs to sort this out. Although this was seriously
considered, the effort was not believed to be justified given the
evident lack of effect of TSC on O2 transport, which
remains the major focus of the study. Prior work from Johnson's laboratory in similar dogs has shown no effect of ordering on cardiopulmonary variables, so the possibility exists that these are
TSC-mediated effects. The CO2 results, however, do point
out a limitation of the present study design, since TSC was always studied during the second bout of exercise. The reason for not reversing the order (of giving buffer vs. TSC) was the prolonged duration of effect reported in earlier work, approaching 200 min (10).
Differences in A/ inequality between the
first and second exercise bouts.
A/ matching improved, as shown by the
dispersion of the perfusion distribution (Fig. 4). This was seen at
rest and during exercise, and the overall effect was highly significant
(P < 0.001). The quantitative improvement was very
small, however, reducing log SD by only 0.05 unit
from 0.48 to 0.43 (averaged over all conditions). As shown in Fig. 3,
this would have raised arterial PO2 by just 1 Torr, with all other factors unchanged. As with the above-mentioned
effects of TSC on CO2, it is possible
that this improvement was due to TSC. However, it is also possible that
the prior effects of the first, control exercise runs were in some way
responsible for the A/ changes independently
of TSC. There were no differences in total ventilation or cardiac
output pre- vs. post-TSC (Fig. 2), nor was there a difference in
pulmonary artery pressure to explain the A/
changes. Domino et al. (3) reported that acidosis improves
A/ relationships. Because there were no
differences, before and after administration of TSC, in arterial (or
mixed venous) pH at any exercise level, acidosis cannot account for the
small improvement in A/ relationships seen in
the present study. Again, although no explanation for the reduced log
SD is apparent, a complete rerun of the protocol
without TSC would be required to determine whether a prior bout of
exercise or TSC is the explanation. It was believed that this was not
justified on the basis of the minor effects on
A/ matching.
Effect of pneumonectomy/lobectomy on response to TSC.
Because lung gas-exchange surface area was reduced after pneumonectomy
or lobectomy, it is possible that diffusion of O2 through plasma may contribute less to total diffusive resistance in
pneumonectomized/lobectomized dogs than in normal animals. Figure
6 explores this possibility by presenting
arterial PO2 before and after TSC during heavy
exercise in each animal studied. There was no difference in the effects of TSC on arterial PO2 as a function of
surgical state. This further suggests lack of diffusive enhancement of
O2 transport by TSC.
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ACKNOWLEDGEMENTS |
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We thank Richard Hogg and Deborah Tuttle for assistance with animal care and training.
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FOOTNOTES |
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This work was supported by Allos Therapeutics (Denver, CO) and National Heart, Lung, and Blood Institute Grant HL-17731.
Address for reprint requests and other correspondence: P. D. Wagner, Div. of Physiology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623A (E-mail: pdwagner{at}ucsd.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 17 May 1999; accepted in final form 14 February 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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