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Pulmonary and Critical Care Division, Department of Medicine, Case Western Reserve University, and Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Van Lunteren, Erik, Augusto Torres, and Michelle Moyer.
Effects of hypoxia on diaphragm relaxation rate during fatigue. J. Appl. Physiol. 82(5):
1472-1478, 1997.
Skeletal muscle fatigue is associated with a
slowing of relaxation rate. Hypoxia may increase the rate at which
fatigue occurs, but, surprisingly, mild to moderate hypoxia has not
been found to augment the degree of slowing of relaxation during
fatigue. The present study tested the hypothesis that severe hypoxia
interacts with fatigue in slowing the rate of muscle relaxation and
that this can be modulated by altering membranous ionic conductances.
Rat diaphragm muscle strips were studied in vitro while aerated with
95% O2-5%
CO2 (normoxia) or 95%
N2-5%
CO2 (hypoxia). During continuous
0.1-Hz stimulation, relaxation rate and force remained stable over
time, and relaxation rate was not slowed by hypoxia. Hypoxia
accelerated force decline during continuous 5-Hz but not intermittent
20-Hz stimulation. During both 5- and 20-Hz stimulation, relaxation
rate became slower over time as force declined, the extent of which was
increased significantly by hypoxia. The extent of hypoxia-augmented
slowing of relaxation rate during fatigue increased over time and was greater than expected for a given degree of force loss. 4-Aminopyridine did not attenuate or partially attenuated, whereas lowering
extracellular Cl
concentration fully attenuated, the hypoxia-induced prolongation of
relaxation rate during repetitive stimulation. Thus
hypoxia slows relaxation rate to a greater extent than expected for a given degree of force decline, an effect that increases over time, is
at most partially attenuated by lowering
K+ conductance, and is fully
attenuated by lowering membranous
Cl conductance.
skeletal muscle; contraction; potassium conductance; chloride
conductance
INTRODUCTION THE RATE at which skeletal muscle relaxes slows as a
muscle fatigues (7, 11, 12, 16, 18, 23). This has been attributed to
several factors, including depletion of high-energy phosphates, intracellular acidosis, and alterations of membranous ionic
conductances (the latter leading to slowing of action potential
repolarization). Muscle repolarization is regulated by
K+ and
Cl Hypoxia has been found to either not affect or accelerate skeletal
muscle fatigue (2, 9, 14, 15, 20). Detrimental effects of hypoxia on
force during fatigue appear to be more prominent with greater degrees
of hypoxia and with higher intensity muscle contraction (2, 20).
Surprisingly, mild to moderate hypoxia does not further slow skeletal
muscle relaxation rate during fatigue, even when force is affected
adversely by hypoxia (2, 9, 20). Whether severe hypoxia might slow
skeletal muscle relaxation rate is not known, but this possibility is
suggested by the finding of slowed rate of relaxation by severe hypoxia
in cardiac muscle (13).
The purpose of the present study was to test the overall hypothesis
that severe hypoxia further slows the rate of diaphragm relaxation
during fatigue. In addition, we tested the hypotheses that the
hypoxia-induced slowing of relaxation during fatigue increases over
time, is more prominent at higher rates of muscle stimulation, and is
altered by changing membranous K+
and Cl METHODS Sprague-Dawley rats (male, weight 200-250 g) were anesthetized
with urethan (1-1.5 g/kg administered ip). The costal diaphragm was removed surgically and placed in room temperature, oxygenated physiological solution. Small strips of muscle (diameter 1-1.5 mm)
were dissected, with the bony and tendinous origins and insertions kept
intact. The muscle strips were mounted vertically and bathed in
physiological solution (temperature 37°C) of the following composition (in mM): 135 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 1 NaH2PO4, 15 NaHCO3, and 11 glucose, with
the pH adjusted to 7.35-7.45 while the solution was being aerated
with 95% O2-5%
CO2. Muscle strips underwent field
electrical stimulation (pulse width 1 ms, supramaximal voltage) via
platinum electrodes, and their length was adjusted to that at which
twitch force was maximal. With this stimulation paradigm, addition of
curare (0.025 mM) to the bath does not alter twitch force, indicating
that the muscles were activated directly (23, 24). To verify that
neurotransmission failure did not contribute to fatigue, diaphragm
force decline was compared in the absence and presence of curare during
repetitive 20-Hz stimulation. If neurotransmission failure were
present, the rate of fatigue should have been faster in the absence
than in the presence of curare, but this was found not to be the case
(Fig. 1). Isometric force was measured with
a high-sensitivity force transducer (Kent Scientific/Radnotti Glass
Technology, Monrovia, CA), and force records were digitized, collected
on-line (Axotape software, Axon Instruments, Foster City, CA), and
stored on the hard drive of a computer for later data analysis.
Five separate experiments were performed, the sample sizes of which are
indicated in Table 1. Muscle
strips were randomized across arms of a given experiment but not across
experiments. After a 15-min equilibration period, muscles underwent
twitch stimulation at 0.1 Hz for a 3-min baseline period. Strips in
which force changed by >5% during the baseline period were discarded from further analysis. After the baseline period, addition of 0.3 mM
4-aminopyridine to block K+
channels (6, 17) (or placebo) was performed in
experiments C and
E, and lowering bath
Cl Table 1.
Stimulation frequencies, experimental conditions, and sample sizes of
the five experiments
conductances, and
lowering either one of these conductances enhances the degree of
slowing of relaxation during fatigue (12, 23).
conductances.
Fig. 1.
Comparison of diaphragm muscle force decline in presence and absence of
curare (0.025 mM) in muscle bath. Force is presented in absolute values
and after normalization to twitch force preceding onset of intermittent
20-Hz stimulation (train duration 0.33 s, with 1 train delivered every
second). n, No. of muscle strips. There were no significant effects of curare on force or half relaxation time.
[View Larger Version of this Image (17K GIF file)]
concentration from 135 to 67.5 mM by substituting Na-gluconate for NaCl to lower
Cl conductance (12) (or no
change in bath Cl
concentration) was performed in experiment
D. A second equilibration period ensued, 4 min for the
4-aminopyridine studies (23) and 5-min for the
low-Cl studies (based on
Ref. 12). Subsequently, the gas with which the solution
was aerated was either switched to 95%
N2-5%
CO2 (hypoxia) or maintained at
95% O2-5%
CO2 (normoxia control). Bath oxygen was monitored in a subgroup of studies with a dissolved oxygen
meter (model ISO-2, World Precision Instruments, Sarasota, FL). Muscles
underwent continued 0.1-Hz stimulation during all of the above
experiments to monitor twitch force. Finally, strips underwent one of
three stimulation protocols (Table 1): continued 0.1-Hz stimulation
(experiment A), continuous 5-Hz
stimulation (experiments B-D),
or intermittent 20-Hz stimulation (train duration 0.33 s, with 1 train
delivered every second; experiment
E). Drugs and reagents were obtained
from Sigma Chemical (St. Louis, MO).
Experiment
A
B
C
D
E
Stimulation frequency, Hz
0.1
5
5
5
20
Experimental conditions
N
(5) H (5)
N (5) H (5)
N-ND (7) H-ND (7)
N-NC
(6) H-NC (6)
N-ND (5) H-ND (5)
N-AP (7)
N-LC (6)
N-AP (5)
H-AP (7)
H-LC (6)
H-AP (5)
Nos. in parentheses are sample size. N, normoxia; H, hypoxia; ND,
no drug; AP, 4-aminopyridine; NC, normal chloride; LC, low chloride.
Data analysis was performed off-line with use of manually controlled
cursors and included measurements of peak force and twitch half
relaxation time (time for force to decay by 50%) performed at 10-s
intervals after the onset of stimulation. Analysis was restricted to
the first 60 s of repetitive stimulation, based on the following
considerations: a desire to avoid long periods of stimulation
associated with large degrees of muscle fatigue and a need to examine
data for the 4-aminopyridine studies when the drug effect was at a
stable plateau. (For Fig. 6 only, half relaxation time was analyzed as
a function of specific degrees of force decline. Measurements of half
relaxation time were performed at the points where force had declined
by 10, 20, and 30% of initial force. This range of force declines was
chosen because it corresponded roughly to the extent of force decline
over 60 s in normoxic muscle.) During the 20-Hz stimulation paradigm,
half relaxation times were derived from the last twitch of each train.
Force values are presented in absolute terms and after normalization
relative to the last three twitches of the 3-min baseline period (23).
Normalization of force values was performed to factor out the effects
of variability in muscle strip size and hence baseline force;
statistical analysis of force data was, therefore, performed only for
normalized values. Data reported are means ± SE. Statistical
comparisons were made with two-way analysis of variance (ANOVA) or
two-way repeated-measures ANOVA followed by the Newman-Keuls test when
the ANOVA indicated statistical significance. A
P value of < 0.05 (2 tailed) was considered to indicate statistical significance.
RESULTS
Changing the gas with which the physiological solution was bubbled from
one containing 95% O2 to one
containing 0% O2 produced a rapid
fall in bath oxygen saturation, which reached a nadir at <5% (Fig.
2). Hypoxia did not significantly reduce
force or slow the relaxation rate of muscle strips undergoing twitch
contractions (i.e., those stimulated at 0.1 Hz; Fig.
3).
The interactive effects of repetitive stimulation and hypoxia on mean
values for force and half relaxation time during 5- and 20-Hz
stimulation are depicted in Figs. 4 and
5. Neither force nor rate of relaxation was
affected by hypoxia at the beginning of repetitive stimulation. During
5-Hz stimulation, normalized force was significantly lower in hypoxic
muscle than normoxic muscle 30-60 s after the onset of
stimulation, whereas hypoxia did not affect normalized force during
20-Hz stimulation (Fig. 4). During both 5- and 20-Hz stimulation
protocols, hypoxia signficantly slowed the rate of relaxation during
the second half of the stimulation period (Fig. 5). During 20-Hz
stimulation, normalized force was comparable for hypoxic and normoxic
muscle, yet half relaxation time was significantly longer for hypoxic
than normoxic muscle (see 40- to 60-s data in Figs. 4 and 5),
indicating that the degree of hypoxia-augmented slowing of relaxation
was greater than expected for a given degree of force decline. To
examine whether this was also the case for 5-Hz stimulation, we
quantified changes in half relaxation time as a function of degree of
force decline (Fig. 6). Hypoxia prolonged
half relaxation time significantly when force had declined by 30% of
initial force, and similar trends were noted for smaller degrees of
force decline. The degree to which relaxation time was prolonged at the
end of the 60-s stimulation period was greater during 20- than 5-Hz
stimulation under both normoxic and hypoxic conditions (Fig.
7).
, or change in
stimulation parameters). Here and in Figs. 5 and 6, 5-Hz data are
combined from experiment B, no-drug
arms of experiment C, and
normal-Cl arms of
experiment D; 20-Hz data are from
experiment E. * Statistically significant changes compared with start of stimulation
(time 0), P < 0.05. # Statistically significant
difference between normoxia and hypoxia for normalized force,
P < 0.05.
arms of
experiment D; 20-Hz data
are from experiment E.
* Statistically significance difference compared
with normoxia, 5 Hz, P < 0.05. # Statistically significant
difference compared with hypoxia, 5 Hz,
P < 0.05. + Statistically significant
differerence compared with normoxia, 20 Hz,
P < 0.05.
In both normoxic and hypoxic muscle, 4-aminopyridine (0.3 mM) had
either no effect (5-Hz stimulation; Fig. 8)
or a small effect (20-Hz stimulation; Fig.
9) on relaxation rate at the onset of repetitive stimulation. After 60 s of stimulation, however, relaxation rate was prolonged substantially by 4-aminopyridine during both 5- and
20-Hz stimulation, as was reported previously for normoxic muscle (23).
In the absence of 4-aminopyridine, hypoxia prolonged relaxation time
significantly after 60 s of both 5- and 20-Hz stimulation. In the
presence of 4-aminopyridine, hypoxia still prolonged relaxation time
significantly after 60 s of 5-Hz contraction. However, the
hypoxia-induced prolongation of relaxation time in the presence of
4-aminopyridine was small and not statistically significant during
20-Hz stimulation.
In normoxic muscle during 5-Hz stimulation, lowering extracellular
Cl did not change
relaxation time at the onset of repetitive contraction. However, the
change in half relaxation time over 60 s of repetitive contractions was
greater under low-Cl than
normal-Cl conditions (Fig.
10). In contrast, lowering extracellular
Cl had no effect on the
change in relaxation time with repetitive stimulation of hypoxic
muscle. With normal extracellular
Cl, there was a greater
change in relaxation time after 60 s of repetitive stimulation during
hypoxia than normoxia, whereas with low extracellular
Cl there was no apparent
effect of hypoxia on the change in relaxation time after repetitive
stimulation.
on half relaxation time
during 5-Hz stimulation. Values are means ± SE and are shown for
relaxation time at onset of and after 60 s of repetitive contraction as
well as for changes in relaxation time over course of 60 s;
n, no. of muscle strips. Data are from
experiment D. * Statistically
significant difference compared with normoxia, normal
Cl,
P < 0.05.
DISCUSSION
conductances.
Muscle relaxation results from reuptake of
Ca2+ into the sarcoplasmic
reticulum, a process that requires energy (3, 4, 7). Studies of fatigue
under normoxic conditions have attributed slowing rate of relaxation to
metabolic factors. Specifically, the degree of relaxation slowing has
been found to be related to intracellular phosphocreatine, creatine,
inorganic phosphate, ATP, and H+
concentrations as well as to rate of ATP hydrolysis (7). Thus possible
explanations for the greater effects of severe than mild to moderate
hypoxia on rate of relaxation during fatigue include an accelerated
rate of intracellular acidosis or an accelerated rate of depletion of
high-energy phosphates. However, in the present study during 20-Hz
stimulation, the relaxation rate was slowed to a greater extent during
hypoxia than normoxia despite comparable changes in force (see
especially 40 s after onset of stimulation, Figs. 4 and 5), arguing
against metabolic factors being the sole determinant of the augmented
slowing of relaxation.
Relaxation may also be prolonged by increased sarcoplasmic
Ca2+ and by delayed repolarization
(5). Repetitive contractions and hypoxia both lead to resting membrane
depolarization, the former as a direct consequence of enhanced
K+ efflux (21, 25) and the latter
possibly as a result of an adenosine-mediated reduction in Na-K pump
activity (10). Repetitive muscle contraction also is associated with
decreased membrane Cl
conductance and slowing of action potential repolarization (12, 16,
18). Lowering Cl
conductance (by reducing extracellular
Cl) and blocking
K+ channels (with 4-aminopyridine)
each slows the rate of relaxation to a greater extent in fatigued than
nonfatigued muscle (Refs. 12, 23; and confirmed by the present data),
suggesting that reduced Cl
and K+ conductances with
consequential delayed action potential repolarization may play roles in
the prolongation of relaxation during fatigue (12, 23).
4-Aminopyridine and low extracellular
Cl had a similar impact on
relaxation rate of resting hypoxic compared with normoxic muscle, which
is not unexpected given that hypoxia itself also did not alter
relaxation rate in resting muscle. The two interventions did affect
relaxation of hypoxic, fatigued muscle, although in different manners:
K+ channel blockade did not
attenuate (during 5-Hz stimulation) or partially attenuated (during
20-Hz stimulation) the hypoxia-induced slowing of relaxation during
fatigue, whereas lowering
Cl conductance fully
attenuated the hypoxia-induced slowing of relaxation during fatigue. In
normoxic muscle, 4-aminopyridine had a considerably greater effect than
did low extracellular Cl in
slowing relaxation during fatigue. Although both interventions are
known to delay cellular repolarization (1, 12, 17), 4-aminopyridine but
not low extracellular Cl
also prolongs contraction time. As a result, the former but not the
latter will increase Ca2+ influx
during the depolarization phase of the action potential, the reuptake
of which will be prolonged, leading to a slower rate of relaxation.
This additional mechanism may account for the greater effects of
4-aminopyridine than low-extracellular
Cl concentration on slowing
the rate of relaxation during fatigue.
That hypoxia further slows rate of relaxation during fatigue even in
the presence of K+ channel
blockade suggests that hypoxia and fatigue may act similarly in
altering K+ channel conductance
and thereby relaxation rate. During 5-Hz stimulation, hypoxia and
4-aminopyridine interacted additively or possibly even multiplicatively
to prolong relaxation rate during fatigue, whereas during 20-Hz
stimulation the effects of hypoxia and 4-aminopyridine singly were
greater than their combined effects. This is consistent with mechanisms
in addition to altered K+
conductance (e.g., metabolic factors) playing a greater role in
determining rate of relaxation during high- than during low-intensity contraction. In contrast, the finding that lowering
Cl conductance exaggerates
the slowing of relaxation during fatigue but attenuates the
hypoxia-induced slowing of relaxation during fatigue argues that
fatigue and hypoxia have divergent effects on the manner in which
Cl conductance regulates
muscle relaxation rate.
Conclusions.
In summary, the present study demonstrated that hypoxia produces a
slowing of relaxation in actively contracting, but not in relatively
quiescent, diaphragm muscle. The augmented slowing of relaxation by
hypoxia during fatigue becomes more prominent over time and appears to
be more pronounced during high- compared with low-frequency
stimulation. Finally, the extent of slowing of relaxation is influenced
by 4-aminopyridine and lowered extracellular Cl concentration,
suggesting a role for altered membranous ionic conductances in the
hypoxia-augmented slowing of relaxation.
ACKNOWLEDGEMENTS
This study was funded by National Heart, Lung, and Blood Institute Specialized Center of Research Grant HL-42215 in Cardiopulmonary Disorders During Sleep and by the Veterans Affairs Medical Research Service.
FOOTNOTES
Address for reprint requests: E. van Lunteren, Pulmonary Sect. 111J(W), Cleveland Veterans Affairs Medical Center, 10701 East Blvd., Cleveland, OH 44106.
Received 1 September 1995; accepted in final form 21 November 1996.
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