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-ENaC transgenic mice: a model for
pulmonary edema
1 Institut de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne; 2 Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The amiloride-sensitive epithelial
Na+ channel (ENaC) is essential for fluid clearance from
the airways. An experimental animal model with a reduced expression of
ENaC, the 
-ENaC transgenic rescue mouse, is prone to develop edema
under hypoxia exposure. This strongly suggests an involvement of ENaC
in the pathogenesis of pulmonary edema. To investigate the pathogenesis
of this type of edema, primary cultures of tracheal cells from these
mice were studied in vitro. An ~60% reduction in baseline
amiloride-sensitive Na+ transport was observed, but the
pharmacological characteristics and physiological regulation of the
channel were similar to those observed in cells from wild-type mice.
Aprotinin, an inhibitor of serine proteases, blocked 50-60% of
the basal transepithelial current, hypoxia induced downregulation of
Na+ transport, and 
-adrenergic stimulation was effective
to stimulate Na+ transport after the hypoxia-induced
decrease. When downregulation of ENaC activity (such as observed under
hypoxia) is added to a low "constitutive" ENaC expression, the
resulting reduced Na+ transport rate may be insufficient
for airway fluid clearance and favor pulmonary edema.
epithelial sodium channel; sodium channel; mouse model; gene targeting; transgenic; Scnn1a
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN HUMANS, PULMONARY EDEMA is a severe condition with a high death rate. It results from an imbalance between alveolar fluid production and clearance, which results in alveolar space flooding. There is a large body of evidence supporting the hypothesis that active Na+ transport across alveolar epithelium in vivo contributes to both reabsorption of the fetal fluid during the postnatal period and maintenance of the adult alveolar spaces free of fluid (for review, see Ref. 19). Inhibition of ion transport might cause a reduced clearance of Na+ and water from alveolar fluid and, therefore, contribute to the formation of alveolar edema. Clinical evidence for a possible defect in Na+ reabsorption was indeed recently reported in subjects susceptible to high-altitude pulmonary edema (28, 33). These subjects had decreased transepithelial nasal potential difference (PD) and a decreased amiloride-sensitive component of the PD in normoxia relative to nonsusceptible control subjects.
In very premature infants, several studies clearly indicated that,
in addition to a relative surfactant deficiency, immaturity of the
liquid absorptive transport system may be an important factor in the
pathogenesis of the respiratory distress syndrome (2, 21).
Nasal transepithelial PDs (PDte) were measured in preterm
infants, demonstrating that impairment of Na+ absorption is
a major determinant of respiratory distress syndrome (2).
Inactivation of the mouse -epithelial Na+
channel (ENaC) gene (Scnn1a) locus by gene targeting in
mouse embryonic stem cells revealed the crucial role of this channel in
lung liquid clearance at birth (12). -ENaC-deficient
neonates developed respiratory distress and died within 40 h after
birth. In those animals, amiloride-sensitive electrogenic
Na+ transport was completely abolished (12).
This suggests that channels made of - and 
-ENaC subunits do
not confer enough Na+ transport activity to
substitute for the normal -, -, or -ENaC function in the lung.
Because of the neonatal mortality of the -ENaC mice, this model did
not allow to address the question of the role of ENaC in the adult
lung. We then generated another animal model by reintroducing a rat
-ENaC transgene under a heterologous cytomegalovirus promoter into
the -ENaC knockout (Scnn1atm1) background
(13). These animals no longer died because of a failure in
lung liquid clearance. They showed near-normal wet-to-dry lung weight
ratios in the postnatal period but presented reduced Na+
channel activity in colon in vivo (to ~20% of wild type)
(13). These mice, however, exhibit a predisposition to at
least two forms of pulmonary edema: thiourea- and hypoxia-induced edema (Hummler et al., unpublished observations; Refs. 9, 10,
17). In addition, under hypoxic conditions [inspired
oxygen fraction (FIO2) of 0.08],
these mice suffer from a defective transepithelial ENaC-mediated
Na+ transport and a diminished alveolar liquid clearance
(9, 10). This strongly suggests that
ENaC-mediated Na+ transport is also important in adulthood,
at least under some kind of specific conditions.
Although we have previously shown that adult
transgenic rescue mice (-ENaC
/Tg+) have a reduced
ability to transport Na+ in their colon (lower
amiloride-sensitive PDte) and probably in their kidney
[persistent pseudohypoaldosteronism type 1 (PHA-1) syndrome
(12)], it is presently not known how the rate
of Na+ transport by airway epithelial cells and
its regulation are affected in adult transgenic rescue mice
(-ENaC/Tg+) compared with wild-type animals. We therefore
evaluated the transepithelial transport of Na+ in primary
cultures of tracheal cells isolated from mice with wild-type and
mutated ENaC alleles under baseline conditions or its response to
physiological, pathophysiological, and pharmacological stimuli. Clarke
et al. (6) showed that the pattern of bioelectric responses to transport inhibitors and ion substitutions in mouse trachea indicate the presence of basal Na+ and
Cl
conductance in the apical membrane. The response to
the Na+ channel blocker amiloride indicates that
Na+ absorption is a major basal ion transport activity
(6). Here, we studied the pharmacological properties of
these altered channels and their response to various regulatory factors
or physiological situations, such as adrenergic stimulation
(terbutaline), effect of protease inhibitors, or hypoxia. Our data show
that -ENaC/Tg+ mice have a low level of ENaC expression but seem
to respond normally to various stimuli, which suggests that the
absolute level of expression is responsible for the phenotype rather
that an abnormal regulation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animal groups.
Protocols involving animals were reviewed and approved by the state
authorities (Service Véterinaire Cantonal, Lausanne, Switzerland). Transgenic rescue mice
(Scnn1atm1/Scnn1atm1TgrENaC),
-ENaC heterozygous mutant (Scnn1atm1/+) and
-ENaC wild-type (Scnn1a+/+) mice were
obtained by interbreeding mice heterozygous mutant for -ENaC allele
[Scnn1atm1 (14)] ± the transgene
Tgr ENaC on a NMRI genetic background. Polymerase chain reaction
(PCR)-based genotyping for the gene targeting status (+/+, +/, and
/) and the transgene (Tg+, Tg) was performed by using specific
primers as described (13). Animals were kept under
standard light (12:12-h light-dark cycle) and standard food conditions
with free access to tap water.
Cell culture and transepithelial current measurements under
normoxic and hypoxic conditions.
Primary tracheal cells were cultured at 37°C, 5% CO2, in
humidified incubators in Ham's F-12 based medium (Life Technologies) containing 1 µg/ml insulin, 7.5 µg/ml transferrin, 1 µM
hydrocortisone, 30 nM 3,5,3,'-triiodothyronine, 1 ng/ml cholera toxin,
2.5 ng/ml epidermal growth factor, 10 ng/ml endothelial cell growth
substance, and 50 nM retinoic acid supplemented (1:1) with STO
fibroblast-conditioned Dulbecco's MEM (Life Technologies) containing
2% FBS principally as described (6). If not otherwise
stated, all substances were obtained from Sigma Chemical, Germany.
Cells were seeded at a concentration of 104 on permeable
collagen-coated filters (Transwell-COL, 6.5-mm diameter, Costar) to
ensure high rates of basal transport. After the fourth day in culture,
the PDte (in mV) and transepithelial resistance (Rte; 
/cm2) were measured by
using the double-electrode system (Millicell-ERS, Millipore). The
equivalent transepithelial short-circuit current (Isc; µA/cm2) was calculated from
the relationship Isc = PDte/Rte. Hypoxic (FIO2 = 0.01, balance
N2) exposures were performed in a Bioblock Scientific
three-gas incubator at 37% for 6-h periods. Culture preparations were
routinely studied within 1-2 days of the development of the
maximal resistance, i.e., 7-10 days after seeding.
RT-PCR analysis.
RT-PCR was performed on total RNA from primary culture of tracheal
cells from newborn and adults and whole lung tissue from adult mice.
Briefly, 3 µg of total RNA were treated with DNase I (Roche,
Switzerland) followed by RT using Superscript II (Life Technologies)
and random primers (Pharmacia). PCR was performed by using 1/10 of the
cDNA digested with RNase (Life Technologies) at 55°C for 15 min. PCR
was done in 50-µl reactions that contained 1.5 mM MgCl2,
50 mM KCl, 10 mM Tris · HCl, pH 8.3, 150 µM of
each deoxynucleoside 5'-triphospate, 0.5 µM of each primer, and 2.5 U
of Taq DNA polymerase (Roche, Switzerland). Forty cycles
each consisting of 30 s at 94°C, 30 s at 48°C, and 1 min
at 72°C were run by using primers for -, -, and -ENaC
(Scnn1a, b, c) as described
(12). Amplified PCR products were separated on a 1.2% agarose gel visualized by ethidium bromide staining.
Pharmacological Tools
Amiloride.
Confluent primary culture of tracheal cells were treated with
increasing concentrations (109 to 103 M) of
amiloride in the apical side solution, and PDte and
Rte were measured after a 15-min incubation in
each amiloride concentration. In part of the experiments, 100 µM ATP
was added in the presence of 100 µM amiloride for 1 min to the apical
side, and Isc was measured.
Aprotinin. Tracheal cells were incubated with 100 µg/ml of aprotinin in the apical side solution. After 6 and 24 h of incubation, Isc was measured.
Terbutaline.
Tracheal cells were incubated with 100 µM terbutaline in the
basolateral solution, a -adrenergic agonist, and
Isc was measured after 5, 10, 15, and 30 min, 1 and 2 h, and 1 and 2 days.
Calculations and Statistics
All data are expressed as means ± SE. Values of n refer to the number of replicate cultures in each group. Individual groups were compared by using Student's t-test for all pairwise comparisons. A level of P
0.05 was
accepted as statistically significant for all comparisons.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Expression of ENaC Subunits in Primary Tracheal Cells
RT-PCR analysis demonstrated the expression of all three ENaC subunits in primary tracheal cells from littermates with different genotypes arising from-ENaC heterozygous mutant ± -ENaC
transgenic interbreeding (Fig. 1).
-ENaC/ (knock out, Scnn1tm1
homozygous mutant) mice lack -ENaC mRNA transcripts (Fig. 1). mRNA transcripts for - and -ENaC were present independent of the
genotype (Fig. 1). Expression of the rat -ENaC transgene was also
clearly detectable in cells from transgenic animals.
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Amiloride Sensitivity in Primary Tracheal Cells from ENaC Mutant and Wild-Type Mice
As shown in Fig. 2A, the equivalent Isc had a significantly lower baseline value in tracheal cells from-ENaC transgenic rescue mice
[2.6 ± 0.6 µA/cm2 (/Tg+) vs. 7.4 ± 1.0 µA/cm2 (+/+ and +/), i.e., ~40% of
wild-type activity, P < 0.001]. However, the
sensitivity to amiloride was similar in the -ENaC/Tg+ mice
(KI = 0.33 ± 0.02 µM, n = 3) and in the -ENaC+/+ and -ENaC+/ mice (pooled values in these
two groups KI = 0.38 ± 0.09, n = 6). The amiloride-insensitive current was similar in all groups.
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Application of ATP in the presence of amiloride resulted in an increase
of Isc most likely due to Cl
secretion (+/+: Isc = 3.4 ± 1.24;
n = 4 vs. /Tg: Isc = 5.2 ± 0.47; n = 3).
Effect of Protease Inhibition
Twenty-four-hour incubation of primary tracheal cells with aprotinin (100 µg/ml), an inhibitor of serine proteases, significantly reduced Na+ transport independently of the ENaC genotype. In wild-type (+/+) mice, Isc decreased by ~60% in heterozygous mutant (+/) and by ~50%
in transgenic rescue mice (/Tg+) (see Fig. 2B for
the absolute values). The effect of aprotinin on transepithelial
current was slowly reversible (data not shown).
Effect of Terbutaline on Transepithelial Na+ Transport Under Normal and Hypoxic Conditions
To further study the regulation of transepithelial transport, we measured PDte and Rte in the three different genotypes on-adrenergic stimulation. We first established
that a significant stimulation of Isc could be
observed in primary tracheal cell culture from wild-type animals by
exposure to 100 µM terbutaline. Isc was
significantly increased after 30 min (1.3-fold stimulation, P < 0.05) and reached a maximum 2.2-fold stimulation
after ~2 h of incubation (P < 0.001; Fig.
3A). We then tested the effect of terbutaline (100 µM) on tracheal cells from wild-type mice after a
6-h period of exposure to hypoxia
(FIO2 = 0.01) that led to a decrease
of Isc of ~50% (P < 0.05).
Terbutaline was added for 2 h under hypoxia. Terbutaline induced a
stimulation of Isc to a level approximately
similar to the initial value before hypoxia (Fig. 3B;
P < 0.01 compared with hypoxia alone). Final
measurements of transepithelial current after addition of amiloride
demonstrated a nearly complete inhibition of
Isc, which supports the hypothesis that the
terbutaline-induced increase of Isc was due, at
least to a large part, to an increased rate of Na+
transport (Fig. 3, B and C; P < 0.05).
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Cells from -ENaC/Tg+ mice showed a similar response on exposure
to hypoxia compared with cells from +/+ (49.3%) and +/ (42.8%) mice
(P < 0.001; /Tg+: 48.5% of basal
Isc, P < 0.05; Fig.
4A). In these three groups,
the baseline Na+ transport rate could be completely
restored within 5 days when cells were returned to normoxia
(FIO2 = 0.21; Fig. 4A).
After exposure to hypoxia for 6 h, application of terbutaline (2-h
incubation, still under hypoxia) induced an increase of the
transepithelial current to a level similar to that recorded initially
under normoxia without adrenergic stimulation, and this effect was
observed in the three tested ENaC genotypes; it was even slightly
higher than baseline in cells from -ENaC/ Tg+ mice (Fig.
4B). Final application of amiloride (100 µM) showed again
that ~70% of the terbutaline-stimulated Isc
represents an amiloride-sensitive ENaC-mediated current.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Fluid clearance in lung cells is an active, energy-dependent
process and has been shown to be driven by active transepithelial Na+ transport due to the presence of ENaC in the apical and
Na+ pumps (Na+-K+-ATPase) in their
basolateral membrane. Several lines of evidence show that ENaC
represents the rate-limiting step in Na+ reabsorption in
epithelia of organs like the lung (19). In our present
experimental model, in the -ENaC transgenic rescue mice
(ENaC/Tg+), -ENaC endogenous gene expression has been replaced by transgenic expression from the human cytomegalovirus promoter (Fig. 1 and Ref. 13). Despite the generally lower
ENaC-mediated Na+ transport that might be explained by
variegated expression of the transgene or by the absence of
corresponding regulatory sequences in the cytomegalovirus promoter,
expression of the transgene resulted in a neonatal phenotypic rescue.
Newborn mice were able to clear their lungs of liquid, and, under
normoxic conditions, adult mice exhibit a near-normal wet-to-dry lung
weight ratio (13). Recent findings demonstrated
that -ENaC dysfunction in these mice impairs alveolar fluid removal
and predisposes the mice to lung edema. Under hypoxic conditions,
-ENaC/Tg+ mice develop pulmonary edema, indicated by an
increased wet-to-dry lung weight ratio (Egli et al., unpublished
observations; Ref. 10). In our present cell culture study,
we were interested to study the underlying mechanism(s) that predispose
to edema formation in this mouse model with altered ENaC function.
In tracheal cells from -ENaC/Tg+ mice studied in
culture, we observed a lower total and amiloride-sensitive
transepithelial Isc, which reflects a
significantly lower ENaC-mediated Na+ transport similar to
what has already been reported for the rectal epithelium in vivo (Figs.
2-4; Ref. 13). Incubation of renal or airway cells
with aprotinin, a serine protease inhibitor, has been shown to result
in a decreased amiloride-sensitive ENaC-mediated transport in several
types of epithelia, and this effect has been attributed to inhibition
of the stimulatory effect of serine proteases like CAP1
(Xenopus, mouse) or prostasin (human) on ENaC activity (8, 29, 32). Further evidence for an action of these
serine proteases came from a recent study in which a recombinant
Kunitz-type serine protease inhibitor efficiently blocked ENaC-mediated
Na+ transport in human bronchial epithelial cells
(4). Our present data are in accordance with these
findings that show that ~50% of the transepithelial current in
primary tracheal cells can be blocked by aprotinin and may require the
activity of a serine protease (Fig. 2B). There was no
obvious difference in the response to aprotinin between wild-type and
-ENaC/Tg+ mice.
The rate of transepithelial Na+ transport can be stimulated
by -adrenergic agonists acting through the cAMP/PKA pathway in respiratory epithelia (5). The exact mechanism by which
cAMP influences Na+ transport in vivo is disputed. Marunaka
et al. (18) found that terbutaline increased the open
probability of an amiloride-sensitive Na+-permeable
nonselective cation channel. In our primary tracheal cells, terbutaline
seems to affect transcription (effect after 30 min) rather than the
open probability (effect within 10 min of exposure) of Na+
channels described by Baxendale-Cox (3) (Fig.
3A). Our data are in accordance with the finding from
Minakata et al. (20), who found that -ENaC mRNA
expression in cultured alveolar type II cells was increased after 2 days exposure to 104 M terbutaline. About 80% of this
transepithelial current was sensitive to amiloride. Different
experimental protocols and/or concentrations applied could also account
for various effects of terbutaline seen in different culture systems
(15, 25). In epithelia from control animals, stimulation
of Na+ transport by terbutaline under hypoxic conditions
resulted in Isc values similar to those observed
under control conditions. With respect to the underlying regulatory
mechanisms, the channels in the -ENaC/Tg+ mice seemed to respond
similarly as those of wild-type cells (Fig. 4B). The
reversal of a hypoxia-induced decrease of Isc by
terbutaline fits with the findings from Vivona et al.
(30). In hypoxic rats
(FIO2 = 0.08), they reported a decrease in transepithelial Na+ and fluid transport that
was reversible by intratracheal instillation of terbutaline
(30). Indeed, the experimental findings match well with
recent clinical studies in humans that showed that prophylactic inhalation of a -adrenergic agonist can reduce the risk of
high-altitude pulmonary edema and that acute inhalation of
-adrenergic agonist achieves therapeutic levels in the pulmonary
edema fluid of ventilated patients with acute respiratory failure
(1, 26). Terbutaline treatment might therefore represent a
potential therapeutic strategy to decrease edema and improve gas
exchange (for review, see Refs. 11, 31).
Hypoxia has been shown to reduce Na+ transport in
airway epithelia, and this effect is due at least in part to
downregulation of ENaC in these cells (7, 22, 23). For
this effect too, the channels of the -ENaC/Tg+ mice seemed
to respond similarly to those of wild-type cells (Fig. 4A). However, because the initial, baseline rate of
transport was lower, the similar reduction resulted in a lower
Na+ transport rate after hypoxia. This very low level of
Na+ transport resulting from the combined effect of the low
level of ENaC expression in -ENaC/Tg+ animals and downregulation due to acute hypoxia might lead to a failure of airway fluid clearance and pulmonary edema.
The -ENaC transgenic rescue mice present a model for renal
salt-wasting syndrome PHA-1. ENaC channel activity derived from transgene expression in the -ENaC/Tg+ mice provides a sufficient amount of Na+ absorptive function in the critical
Na+ absorbing organs, like lung, kidney, and colon
(13). Whereas young -ENaC/Tg+ mice showed clinical
features of severe PHA-1 with metabolic acidosis, urinary salt-wasting,
growth retardation, and 50% mortality within the first 3 wk of life,
adult transgenic rescue mice exhibited a compensated PHA-1 with normal
acid/base and electrolyte values (13). Despite a
diminished Na+ transport in all organs and a decreased lung
liquid clearance, adult transgenic rescue mice showed near-normal
liquid absorption under normoxia (10, 13). Our data
suggest that diminished basal Na+ transport per se is not
sufficient for edema formation but that an additional stress to the
system is necessary for edema to develop. This stress might be a
further reduction of the Na+ transport capacity, such as is
the case in hypoxia, or an increase in fluid production, such as is the
case of toxic or hydrostatic edema.
PHA-1 patients carrying ENaC mutations in all three subunits also have a reduced rate of liquid absorption from airway surface. The result is an increased volume of liquid in the airway that demonstrates that ENaC-mediated Na+ transport has an important role on adult airway surfaces (16, 24, 27). These patients are not known for spontaneous development of pulmonary edema. However, it is not known whether PHA-1 patients might be more prone to develop pulmonary edema when exposed to additional stress.
In conclusion, our observations show that, in our PHA-1 model that
results from the knock out of the endogenous mouse -ENaC gene and
its partial replacement by rat -ENaC, Na+ transport in
the airway epithelia is globally reduced to ~40% of the wild-type
level, but the responses to either pharmacological inhibitors or
physiological regulation are preserved and are proportionally similar
to those observed in tissues from wild-type animals. We propose that,
under circumstances leading to downregulation of ENaC, the rate of
Na+ transport becomes insufficient to maintain fluid
balance, and lung edema may result. In other words, in addition to a
lower basal Na+ transport, a further risk factor is
necessary to generate lung edema in the in vivo models. Transgenic
rescue mice with their ENaC dysfunction present a useful model to study
the involvement of ENaC channels in the pathogenesis of pulmonary edema.
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ACKNOWLEDGEMENTS |
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We thank Friedrich Beermann for critically reading the manuscript and Hans-Peter Gaeggeler for excellent photographic work.
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FOOTNOTES |
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This work was supported by Swiss National Science Foundation Grant nos. 32-51157.97 (Tandem) (to U. Scherrer), 31-061966.00 (to B. C. Rossier), and 31-063801.00 (to E. Hummler).
Address for reprint requests and other correspondence: E. Hummler, Institut de Pharmacologie et de Toxicologie, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland (E-mail: ehummler{at}pop-server.unil.ch).
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.
July 12, 2002;10.1152/japplphysiol.00413.2002
Received 10 May 2002; accepted in final form 9 July 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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