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Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study investigated the relationship between intracellular PO2 (PIO2) and dichloroacetate (DCA) administration following a significant step-change increase in oxidative metabolism in intact isolated Xenopus single muscle fibers. Single fibers (n = 22) were dissected from the lumbrical muscle, injected with the oxygen-sensitive compound palladium-meso-tetra (4-carboxyphenyl) porphine, and randomly assigned to one of two treatment groups. One group (DCA; n = 12) was incubated for 30 min with 1.2 mM DCA, whereas the second group [control (Con); n = 10] was incubated for 30 min in Ringer solution only. After incubation, fibers were electrically stimulated to elicit tetanic contractions (0.5 Hz) for 2 min during which PIO2 was monitored. PIO2 before contractions began was 32.0 ± 1.8 and 29.0 ± 1.8 Torr for DCA and Con, respectively, and fell to 6.0 ± 1.3 and 8.8 ± 2.4 Torr (no significant difference), respectively, after steady state was reached. The kinetics of the fall, determined by both the time delay (from the start of contractions to the initial decrease in PIO2) and the tau (63% of the change to a steady state in PIO2), were calculated. In DCA cells, the tau was significantly (P < 0.05) faster than Con (22.1 ± 3.6 vs. 39.7 ± 5.8 s). In contrast, the time delay was not significantly (P > 0.45) different between the two groups (11.4 ± 1.7 vs. 12.6 ± 2.3 s, respectively). The amount of fatigue, reflected by a decrease in force production from initial, was not significantly different between groups. These data suggest that by stimulating pyruvate dehydrogenase with DCA in isolated single skeletal muscle cells, the faster fall in PIO2 is indicative of oxidative metabolism being more rapidly activated. This is the first evidence that oxygen uptake at the onset of contractions may be altered by DCA during moderate- to high-intensity contractile activity.
oxygen kinetics; oxidative metabolism; pyruvate dehydrogenase; metabolic inertia; fatigue
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MECHANISMS that regulate the onset kinetics of oxidative metabolism at the start of exercise have been well studied in recent years. Much of the research into these mechanisms has focused on whether the rate of oxidative phosphorylation is controlled by so-called exogenous factors, such as blood flow and/or oxygen delivery (26), or by intrinsic factors, such as cellular regulators or metabolic activation (30).
Several studies demonstrated previously that the
administration of dichloroacetate (DCA) under a variety of conditions
results in a decreased reliance on nonoxidative ATP production at the onset of exercise, as reflected in a decrease in both the accumulation of muscle lactate and the decline in muscle phosphocreatine (PCr) content, whether in exercising humans (13, 24) or in
contracting dog muscle (25). As DCA is a stimulator of the
pyruvate dehydrogenase (PDH) complex (29), it has been
suggested that an activation of PDH by DCA allows for greater flux of
carbohydrate-derived carbon into the TCA cycle, allowing for greater
oxygen utilization at the onset of exercise. However, this rise in
oxidative metabolism, while remaining the most likely explanation for
the decrease in nonoxidative ATP production, has yet to be
directly shown experimentally. To date, few studies have attempted to
measure 
O2 on-kinetics with DCA in
working skeletal muscle at the onset of contractions, and these have
found no difference in the rate of increase in O2 in either humans or isolated dog
muscle (1, 9). However, changes in
O2 uptake kinetics may be difficult to measure across contracting human or canine skeletal muscle, and the work intensity employed may be an important factor in whether PDH
activation influences onset kinetics.
Recently, our lab published several papers on the
relationship between intracellular PO2
(PIO2) and muscle contraction in intact Xenopus single skeletal muscle fibers using a
porphyrin phosphorescent probe for the measurement of
PIO2. Initial experiments showed
that PIO2 fell at the onset of
contractions and recovered when contractions ended (11).
This fall was subsequently shown to 1) occur with a rate
constant similar to whole body or isolated muscle
O2 (12), 2) be
more rapid on subsequent bouts following a "priming" contractile
period (12), and 3) to have a magnitude linearly related to stimulation frequency and thus energy demand (15). The results of these previous studies suggest that
our method of measuring PIO2 is
extremely useful for investigating cellular oxidative metabolism in a
skeletal muscle model in which external factors can be tightly controlled.
The purpose of the present study was to quantify the changes in
PIO2 at the onset of
moderate-intensity contractile activity with DCA administration. By
using isolated intact single skeletal muscle fibers, this investigation
avoids many confounding factors that make whole muscle studies
difficult to interpret. Because DCA has been suggested to affect
oxidative metabolism during muscle contractions, our hypothesis was
that PIO2 would fall more rapidly in DCA-treated cells than control (Con) cells, likely reflecting a
faster increase in O2 at the onset of exercise.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal care. All procedures were approved by the University of California San Diego animal care and use committee and conform to National Institutes of Health guidelines. Female adult Xenopus laevis were doubly pithed and decapitated and the lumbrical muscles (II-IV) were dissected free from the hindfeet.
Measurement systems. All dissections and experiments were conducted at 20°C. Single living muscle fibers (n = 22) were microdissected from the lumbrical muscle strips with tendons intact in a chamber filled with Ringer solution (112 mM NaCl, 1.87 mM KCl, 0.82 mM CaCl2, 2.38 mM NaHCO3, 0.07 mM NaH2PO4, 0.1 mM EGTA; pH 7.0). A mix of muscle fiber types was used and these single fibers average ~60-100 µg wet wt. Intact cells were microinjected with a solution of 0.5 mM palladium-meso-tetra(4-carboxyphenyl)porphine bound to bovine serum albumin (containing 10 mM fura-2 for visual monitoring) by micropipette pressure injection (World Precision Instruments PV830 pneumatic picopump, Sarasota, FL). Experiments are only performed on fibers with visually intact plasma membranes that exhibit normal contractile properties and that do not display any difficulties in propagating action potentials in response to electrical stimulation.
Phosphorescence signals were recorded using a Nikon 40× Fluor objective (0.70 numerical aperture) used dry. The phosphorescence quenching of the Pd-porphyrin oxygen probe within each cell was measured through a system consisting of a flash lamp (Oxygen Enterprises, Philadelphia, PA), a 425-nm band pass excitation filter, a 630-nm cut-on emission filter, and a photomultiplier tube for collection of the phosphorescence signal. To calculate phosphorescence lifetimes from the intracellular O2 probe, the phosphorescent decay curves from a series of 10 flashes (15 Hz) were averaged and a monoexponential function was fit to the subsequent best-fit decay curve (analysis software from Medical Systems, Greenvale, NY). Phosphorescent decay curves were recorded every 4 s from each cell throughout the experimental period. Previously determined values for the measured phosphorescence lifetime decay in a zero oxygen environment and the phosphorescence quenching constant for the intracellular oxygen probe were used to calculate PIO2 (11). As the oxygen tension decreases in the environment around the porphyrin compound, the phosphorescence lifetime (after a single flash of light) lengthens in a systematic manner (28). This technique has been previously validated for the measurement of PIO2 within single skeletal muscle cells injected with the porphyrin compound (11). In that investigation, cellular respiration was abolished with inhibitors, allowing the PIO2 to equilibrate with the extracellular PO2. With the use of solutions with known standard PO2, the response of the porphyrin was then calibrated.Experimental protocol. Platinum clips were attached to the tendons of the cells and they were mounted in a chamber filled with Ringer solution. One end of the fiber was fixed and the other free end was attached to an adjustable force transducer (Aurora Scientific, model 400A, Aurora, Ontario), allowing the muscle to be set at a length (Lo) that produced maximal tetanic force (Po). The analog signal from the force transducer was sampled at 200 Hz and converted to a digital signal via an MP100WSW A-D converter and analyzed with AcqKnowledgeIII 3.2.6 analysis software (Biopac Systems, Santa Barbara, CA). Fatigue was standardized by comparing force at the end of the stimulation protocol to the maximal tetanic force (P/Po).
Before stimulation, fibers were incubated in standard Ringer solution (plus 4 mM glucose) with 1.2 mM DCA (n = 12) or without (Con; n = 10) for 30 min. The concentration of DCA for the present study was chosen to be close to the effective concentration resulting from the 100-mg/kg dose used in previous investigations using humans (13, 14) in which PDH activation was shown to be among the highest ever reported. At the start of the stimulation, the chamber was perfused with Ringer equilibrated with a gas mixture to produce a PO2 of ~30 Torr. As the normal in vivo PO2 value surrounding Xenopus skeletal muscle is not known, this PO2 value represents an approximate published mean capillary PO2 value for mammalian tissue (19, 20). Constant perfusion was maintained throughout the protocol to maintain the experimental PO2 and to reduce the possible occurrence of unstirred layers surrounding the cell. Tetanic contractions were elicited using direct (8-10 V) stimulation of the muscle (Grass model S48, Warwick, RI). Stimulation consisted of 200-ms trains of 70-Hz impulses of 1-ms duration. After a resting 20-s initial recording period, fibers were stimulated for 2 min at 0.5 Hz.Calculations.
Data were examined blind to the treatment. All data were plotted for
kinetic fitting of the fall in PIO2
using Kaleidagraph data analysis software (Synergy Software, Reading,
PA). A monoexponential curve fit model incorporating a time delay was
used. It is represented as
![P<SC>o</SC><SUB>2</SUB>(<IT>t</IT>) = P<SC>o</SC><SUB>2</SUB>(b) − A × [1 − <IT>e</IT><SUP>−(<IT>t</IT> − TD)/&tgr;</SUP>]](/content/vol284/issue2/fulltext/R481/img001.gif)
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is the time constant.
Statistics. All values are presented as means ± SE. To test for significance, a Student's t-test for independent samples for each variable was performed between the two groups. The level of significance was set at P < 0.05 throughout.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PO2 kinetic analysis.
Figure 1 shows representative data from a
single DCA and a single Con fiber showing the method of curve fit.
Plotted data were fit with a single time delay and a
monoexponential fall in PIO2. The
model parameters for each fiber are shown on Fig. 1.
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Intracellular PO2.
Figure 2 is a plot of the fall in
PIO2 during the measurement period
for both Con and DCA groups. The mean data for all cells in both
conditions are shown. The more rapid fall in
PIO2 is clearly evident in the DCA
group. Resting PIO2 (32.0 ± 1.8 vs. 29.0 ± 1.8 Torr; DCA vs. Con) and steady-state
PIO2 (6.0 ± 1.3 and 8.8 ± 2.4 Torr; DCA vs. Con) values were not significantly different between groups.
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Time delay.
The time between the onset of electrically stimulated contractions and
the first fall in PIO2 is the time
delay. The lack of significant difference in time delay between groups
is seen in Table 1.
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Tau. The time constant (tau) represents the time to reach 63% of the difference between the higher resting PIO2 and the low steady-state PIO2. Table 1 demonstrates how the time constant for the fall in PIO2 is significantly faster for DCA cells than for Con.
Force. The relative amount of fatigue in both experimental conditions, expressed as the force developed at the end of stimulation compared with initial force production, is shown in Table 1. There was no significant difference in the amount of fatigue produced by 2 min of stimulation between the Con and DCA groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study demonstrated that administration of DCA
to intact single skeletal muscle cells before the onset of contractions
resulted in a significantly faster fall in intracellular PO2 from resting levels during the contractile
period. This is the first evidence that skeletal muscle oxidative
metabolism may be altered by DCA during contractions. Although
O2 was not measured directly in the
present study, due to the relationship between O2 and PO2
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O2 will
rise with any decrease in measured
PIO2 as the other parameters should
remain constant. Previous studies demonstrated that intense electrical
stimulation will elicit a large increase in
O2 in these cells within 1-2 min
(3, 27) and that increased stimulation frequency will
elicit greater falls in PIO2 and
thus increased O2 (15).
In previous studies using DCA administration, the changes in oxidative
metabolism have been inferred from a decrease in nonoxidative ATP
production in working muscle. These changes include decreased PCr
utilization and decreased muscle lactate production (13, 23). Very few studies to date, however, have attempted to
directly measure O2 kinetics with DCA,
and these have demonstrated that faster
O2 kinetics do not appear to occur with
the administration of DCA whether in animal (9) or human
models (1). The reason(s) for the discrepancy between the
present result showing significant changes in the fall in
PIO2 and the failure thus far to
show O2 changes with DCA could be
several. First, it is possible that the differences in oxidative
metabolism between treatments are not large enough to be easily
measured in whole muscle preparations (human or animal). Due to the
efficiency of oxidative metabolism, the relatively large decrease in
nonoxidative ATP production is counterbalanced by very little oxygen
utilization. It may be very difficult to measure such small differences
in O2 caused by DCA administration using
pulmonary or arteriovenous (Fick) measurement of
O2 without repeated measurements during
the crucial period at the onset of exercise. Second,
speeding of oxygen uptake kinetics by various interventions is often,
but not always, seen only when work rate is high (i.e., above lactate
threshold). In contracting dog muscle, when blood flow was kept very
high before the onset of contractions,
O2 kinetics were not significantly
accelerated at submaximal work rates (7) but were at
O2 max (10). This has also
been shown in humans when priming exercise is done (5,
18). In those human studies, differences in
O2 kinetics (primarily via a reduction
in O2 slow component) were present in a
second bout of exercise only when the work rate was above ventilatory
threshold. Conversely, DCA administration has been shown to be
ineffective when exercise is done at higher workloads, such as 110% of
O2 max (1) or during very
intense (>250% O2 max) isokinetic
cycling (14). Therefore, it appears that the range of
intensity is crucial for demonstrating large changes in
O2 kinetics in any model. In the present
study, an isometric contraction frequency was chosen that has
previously been shown to both cause a rapid and large decrease in
PIO2 (15) and also be
sustainable for several minutes (12). Although it is
difficult to precisely quantify the relative intensity of this contraction regime, the rate of fatigue suggests that it is moderate to
heavy domain but likely below that which would elicit
O2 max, even though this would of
course vary somewhat by fiber type. Finally, it is possible that the
effect(s) of DCA are simply easier to measure in a single cell model
where issues of blood flow, fiber recruitment, muscle/blood/expired gas
sampling, and/or drug delivery are negligible.
The present study sheds some light on the current controversy regarding
the control of oxidative metabolism (6, 16). Much has been
written in the past years about whether the rate at which oxidative
phosphorylation activation is controlled by either extrinsic factors
(i.e., blood flow and/or oxygen delivery) or intrinsic factors (i.e.,
activation of key enzymes or "metabolic inertia") (6, 7,
27). However, the exact contribution of intrinsic and extrinsic
factors in vivo can be difficult to assess and is influenced by the
experimental conditions. The isolated single fiber model used for the
present study is optimal for studying this question as extrinsic
factors can be tightly controlled. Unlike in perfused skeletal muscle,
where blood flow distribution may be problematic (6),
there is no heterogeneity of blood flow or oxygen delivery as the
single cell is completely perfused. The present data suggest that even
when extrinsic factors are kept optimal, there is still a delay in the
onset of oxidative metabolism, confirming the previous work done in
single fibers (12). Furthermore, our results suggest that
the rate of activation of oxidative metabolism can be increased by
affecting one of the key enzymes in the pathways, PDH. Metabolic
inertia has been shown previously in studies of isolated dog muscle
when blood flow is enhanced at the onset of contractions
(8) or when offloading of oxygen is increased
(10). In both of those studies, greater delivery of oxygen
did not change O2 kinetics, suggesting
an inherent lag in oxygen utilization distal to oxygen delivery. Likewise, it was demonstrated that microvascular
PO2 does not fall immediately with exercise,
demonstrating that systemic oxygen delivery is not limiting to
oxidative metabolism at the onset of contractions (2).
They further suggest that the delay in O2 onset in that model is therefore due
to metabolic inertia since O2 delivery is sufficient. A
recent study by Kindig et al. (17) used the nitric oxide
(NO) synthase blocker
NG-nitro-L-arginine methyl ester
(L-NAME) during exercise in horses and demonstrated an
acceleration in O2 kinetics. These
authors believe that this is due to relieving a direct inhibition of
oxidative phosphorylation by NO and not due to differences in blood
flow. Because there is evidence that NO may not play a large role in regulating exercise blood flow in humans (22), it is hard
to say if blood flow in the L-NAME condition was depressed
due to blocking the normal vasodilatory effects of NO
(21), but it would certainly not be expected to be any
greater than without L-NAME. Because the model used in the
present study has no intact circulation, our results cannot address
whether blood flow does play a role in affecting
O2 kinetics or not. However, it does agree with previous studies that cellular mechanisms do play a role in
determining oxygen uptake kinetics.
One interesting result from the present study is that the acceleration
in intracellular PO2 reduction due to DCA
occurs primarily due to a decreased time constant (tau) and not due to
a decreased time delay. This is in contrast to a previous study using
this model to look at repetitive contractile periods (12).
In that study, the overall O2 kinetic
response was faster following a prior warm-up series of contractions
due mainly to a relatively large (80%) decrease in the time delay
before activation. One possible explanation for these results is the
loci of metabolic activation in the different protocols. In the present
(DCA) study, PDH is presumably the only activated regulatory enzyme,
whereas in the previous study, downstream regulatory points such as
other dehydrogenases, TCA cycle flux, or cytochromes may be affected by
prior exercise. Why the additional regulatory points would affect
primarily the time delay is not presently known. It is clear that PDH
activation itself is very important in reducing nonoxidative ATP
production at the onset of contractions as demonstrated by several DCA
studies. This is in contrast to increasing only PDH product (i.e.,
acetyl-CoA and acetylcarnitine) alone, which has no effect on PCr or
lactate at the onset of exercise (4).
In summary, the present study demonstrates in single skeletal muscle
fibers that DCA administration will accelerate the fall in
intracellular PO2 at the onset of exercise.
This suggests that PDH activation is a major regulator for oxidative
phosphorylation in these single amphibian fibers. In addition, the
results support several other studies that show that metabolic inertia
certainly does play a role in O2 onset
kinetics in these cells.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-40155. R. Howlett was a National Sciences and Engineering Research Council Canada postdoctoral fellow.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. A. Howlett, Dept. of Medicine 0623A, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: rhowlett{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. Section 1734 solely to indicate this fact.
First published November 21, 2002;10.1152/ajpregu.00078.2002
Received 7 February 2002; accepted in final form 13 November 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 R. A. Howlett, C. A. Kindig, and M. C. Hogan Intracellular PO2 kinetics at different contraction frequencies in Xenopus single skeletal muscle fibers J Appl Physiol, April 1, 2007; 102(4): 1456 - 1461. [Abstract] [Full Text] [PDF]
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 B. J. Gurd, S. J. Peters, G. J. F. Heigenhauser, P. J. LeBlanc, T. J. Doherty, D. H. Paterson, and J. M. Kowalchuk Prior heavy exercise elevates pyruvate dehydrogenase activity and speeds O2 uptake kinetics during subsequent moderate-intensity exercise in healthy young adults J. Physiol., December 15, 2006; 577(3): 985 - 996. [Abstract] [Full Text] [PDF]
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M. Burnley, J. H. Doust, and A. M. Jones Time required for the restoration of normal heavy exercise VO2 kinetics following prior heavy exercise J Appl Physiol, November 1, 2006; 101(5): 1320 - 1327. [Abstract] [Full Text] [PDF]
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C. M. Stary and M. C. Hogan Intracellular pH during sequential, fatiguing contractile periods in isolated single Xenopus skeletal muscle fibers J Appl Physiol, July 1, 2005; 99(1): 308 - 312. [Abstract] [Full Text] [PDF]
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B. J. Gurd, B. W. Scheuermann, D. H. Paterson, and J. M. Kowalchuk Prior heavy-intensity exercise speeds V{middle dot}O2 kinetics during moderate-intensity exercise in young adults J Appl Physiol, April 1, 2005; 98(4): 1371 - 1378. [Abstract] [Full Text] [PDF]
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C. A. Kindig, C. M. Stary, and M. C. Hogan Effect of dissociating cytosolic calcium and metabolic rate on intracellular PO2 kinetics in single frog myocytes J. Physiol., January 15, 2005; 562(2): 527 - 534. [Abstract] [Full Text] [PDF]
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J. A Timmons, D. Constantin-Teodosiu, S. M Poucher, and P. L Greenhaff Acetyl group availability influences phosphocreatine degradation even during intense muscle contraction J. Physiol., December 15, 2004; 561(3): 851 - 859. [Abstract] [Full Text] [PDF]
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M. Endo, S. Tauchi, N. Hayashi, S. Koga, H. B. Rossiter, and Y. Fukuba Facial cooling-induced bradycardia does not slow pulmonary V.O2 kinetics at the onset of high-intensity exercise J Appl Physiol, October 1, 2003; 95(4): 1623 - 1631. [Abstract] [Full Text] [PDF]
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) and DCA (
) groups.
The plot is raw mean data for all cells (error bars omitted for
clarity). Note the more rapid fall in PO2 in
the DCA group. The arrow represents the start of tetanic
contractions.