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1 Nutrition and Metabolism Research Group, Division of Gastroenterology, Department of Medicine and 3 Department of Food Sciences and Nutrition, University of Alberta, Edmonton, Alberta T6G 2C2; and 2 Division of Gastroenterology and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2T5
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Glucocorticosteroids enhance digestive and absorptive functions of the intestine of weaning and adult rats. This study was undertaken to assess the influence of treatment of weaning male rats with budesonide (Bud), prednisone (Pred), or control vehicle on the in vitro jejunal and ileal uptake of glucose and fructose. Bud and Pred had no effect on the uptake of D-glucose by sodium glucose transporter-1. In contrast, the uptake of D-fructose by GLUT-5 was similarly increased with Bud and with Pred. The increases in the uptake of fructose were not due to variations in the weight of the intestinal mucosa, food intake, or in GLUT-5 protein or mRNA expression. There were no steroid-associated changes in mRNA expression of c-myc, c-jun, c-fos, proglucagon, or selected cytokines. However, the abundance of ileal ornithine decarboxylase mRNA was increased with Pred. Giving postweaning rats 4 wk of Bud or Pred in doses equivalent to those used in clinical practice increases fructose but not glucose uptake. This enhanced uptake of fructose was likely regulated by posttranslational processes.
adaptation; budesonide; glucose transporter-5; prednisone; sodium glocose transporter-1
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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GLUCOCORTICOSTEROIDS ("steroids") are widely used to treat a variety of gastrointestinal and hepatic conditions, such as inflammatory bowel diseases and chronic active hepatitis (1-6). However, the systemically active steroids may be associated with potentially serious adverse effects (1, 7-9). The high prevalence of these adverse effects has been a major impetus for the development of nonsystemic steroids. Budesonide is a nonsystemic steroid with high topical activity, low-systemic bioavailability, and rapid first-pass metabolism in the intestine and liver (1, 10). Budesonide is of proven clinical efficacy when given topically or orally to patients with inflammatory bowel disease (11, 12).
In young animals, steroids induce precocious development of some of the
intestinal brush border membrane (BBM) enzymes and facilitate the
induction of specific enzymes by dietary carbohydrate (13-15). Systemically active steroids given by mouth
enhance glucose uptake by adult animals (16).
Dexamethasone (128 µg · kg
1 · day1)
given subcutaneously for 7 days blunts the expected adaptive response
after intestinal resection (17).
The Na+ gradient across the BBM provides the driving force for glucose transport (18). This gradient is maintained by the action of the Na+-K+-ATPase, which is restricted to the basolateral membrane (BLM) of the enterocyte (19). Sodium glucose transporter-1 (SGLT-1) mediates the BBM Na+-glucose cotransport (20-22). Fructose uptake across the BBM is mediated by facilitated diffusion by GLUT-5 (23-26), whereas GLUT-2 mediates the facilitative Na+-independent diffusion of glucose and fructose through the BLM (27). Recent evidence suggests that GLUT-2 may also be in the BBM (28-30).
Proglucagon-derived peptides originate from processing and breakage of the proglucagon gene product (31, 32) in the L-cells present in the ileum and colon (33). Ornithine decarboxylase (ODC) is a key enzyme in the synthesis of polyamines, a requirement for any proliferative event. Early-response genes (ERG) are genes expressed in response to proliferative stimulation. It has been suggested that the mRNA levels of proglucagon and ODC, as well as the mRNAs of ERG such as c-myc, c-jun, and c-fos may be involved in the intestinal adaptive process such as resection of the small intestine (34-37). It is unknown whether proglucagon, ODC, or ERGs in the intestine are influenced by steroids.
A wide variety of cytokines are produced locally by the intestinal epithelium, and they are involved in the homeostasis of the intestinal tissue during development (38, 39). Cytokine gene expression has been shown to be regulated by hydrocortisone and dexamethasone during postnatal small intestinal development (40). Cytokines alter sugar absorption (41-43). It is not known whether the cytokines in the intestine are influenced by prednisone or budesonide.
Accordingly, this study was undertaken to assess the influence of
budesonide and prednisone, in doses equivalent to those used in
clinical practice, on 1) the intestinal uptake of glucose and fructose in young growing rats; 2) the abundance of the
glucose and fructose transporter proteins and the expression of their respective mRNAs; and 3) the mRNA expression of several
potential signals of steroid-associated intestinal adaptation including proglucagon, ODC, three ERGs (c-myc, c-fos, and
c-jun), and selected cytokines (TNF-
, IL-2, IL-6, and
IL-10).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and drugs. The principles for the care and use of laboratory animals, approved by the Canadian Council on Animal Care and the Council of the American Physiological Society, were observed in the conduct of this study. Weanling male Sprague-Dawley rats, 21-23 days of age postpartum, were obtained from the University of Alberta vivarium. Pairs of rats were housed at a temperature of 21°C, with 12 h of light and 12 h of darkness. Water and food were supplied ad libitum. The animals were fed standard Purina rat chow.
It was previously calculated with a reliability coefficient of 95%, a margin of error of 3, and a population standard error (estimation) of 18 that a sample size of eight would be statistically sufficient to detect the differences if they were present. For the dosing study, a sample size of six was determined to be sufficient to detect any major differences between the groups. For the gene expression studies, we used a sample size of three, which allowed us to make preliminary observations. Therefore, negative results should be carefully considered and not discarded, because the sample size may not have been large enough to demonstrate true differences. There were eight animals in each of three groups: 1) control (0.19% EDTA-buffered saline), 2) budesonide (0.25 mg · kg body wt1 · day1), and
3) prednisone group (0.75 mg · kg body
wt1 · day1). The
doses of prednisone and budesonide were chosen on the basis of regimens
that have been shown to be useful clinically in humans (7, 44,
45). The steroids were administrated by oral gavage each day and
were dissolved in 0.19% EDTA-buffered saline. The volume of vehicle
given was 5 µl/g body wt. Animals were gavaged for a duration of 4 wk
with drug or vehicle at 1200 daily, including weekends. This range is
similar to the doses (0.2-0.8
mg · kg1 · day1)
used to treat trinitrobenzene sulphonic acid ileitis in rats (44) and the doses (0.1-1.0
mg · kg1 · day1)
used to prevent graft rejection in a rat model of intestinal transplantation (45).
A dosing study with budesonide was also performed. There were six
animals in each group, and the doses of budesonide that were used were
0.50, 0.75, and 1.00 mg · kg1 · day1 for 2 wk.
Probe and marker compounds. The 14C-labeled probes included L-glucose (16 mM), D-mannitol (16 mM), and a range of concentrations of D-glucose and D-fructose (4, 8, 16, 32, and 64 mM). Unlabeled and 14C-labeled probes were supplied by Sigma Chemical (St. Louis, MO) and by New England Nuclear, respectively. [3H]inulin was used as a nonabsorbable marker to correct for the adherent mucosal fluid volume. Probes were shown by the manufacturer to be >99% pure by high-performance liquid chromatography.
Tissue preparation and determination of uptake rates. The animals were killed by the injection of Euthanyl (pentobarbitol sodium, 240 mg/100 g body wt). The whole length of the small intestine was rapidly removed. The proximal one-third beginning at the ligament of Treitz was termed the jejunum, and the distal one-third was termed the ileum; the middle one-third of the small intestine was discarded. The intestine was everted and cut into small rings of lengths of ~2-4 mm each (46). The rings were immersed immediately in preincubation beakers containing oxygenated Krebs-bicarbonate buffer (pH 7.2) at 37°C and were allowed to equilibrate for ~5 min before commencement of the uptake studies. Uptake was initiated by the timed transfer of tissue rings to a shaking water bath (37°C) containing 5-ml plastic vials with gassed Krebs buffer (95% O2, 9% CO2) plus [3H]inulin and 14C-labeled substrates. After incubation for 5 min, the uptake of nutrient was terminated by pouring the vial contents onto filters immobilized on an Amicon vacuum filtration manifold maintained under suction. This was followed by washing the jejunal or ileal rings with ice-cold saline. The tissue was dried, and the weight was recorded before saponification of the tissue with 0.75 N NaOH. Scintillation fluid was added, and radioactivity was determined by means of an external standardization technique to correct for variable quenching of the two isotopes.
The rates of uptake of the sugars were expressed as nanomoles of substrate taken up per 100 milligrams dry weight of intestinal tissue per minute (nmol · 100 mg tissue1 · min1). The
values obtained from the three treatment groups (control vehicle,
budesonide, and prednisone) were reported as the means ± SE of
results obtained from eight animals in each group.
The values of Vmax and Km
for glucose uptake were estimated by using nonlinear regression (Sigma
Plot program, Jandel Scientific, San Rafael, CA). Because the
relationship between fructose concentration and uptake was linear over
the range of concentrations studied (4-64 mM), the values of
Vmax and Km could not be
calculated. Instead, linear regression was used to obtain the value of
the slope of this linear relationship.
Membrane preparation.
There were eight animals in each of the three drug groups (control,
budesonide, and prednisone). Two 40-cm lengths of proximal jejunum and
distal ileum were rapidly removed and rinsed gently with ice-cold
saline. The intestine was opened along its mesenteric border, and the
mucosal surface was washed carefully with cold saline to remove mucus
and debris. The mucosal surface was blotted with lint-free tissue to
remove excess moisture and was removed from the rest of the intestinal
wall by gently scraping with a microscopic slide and then snap-freezing
the tissue in liquid nitrogen at 
80°C for later membrane
preparation. BBM and BLM were isolated from the rat intestinal mucosal
scrapings by using homogenization, differential centrifugation, and
Ca2+ precipitation (47-49). Aliquots were
stored at 80°C for Western immunoblotting.
Western immunoblotting.
BLM and BBM proteins were separated by SDS-PAGE. After electrophoresis,
proteins were immobilized and transferred to nitrocellulose by
electroblotting. Then the membranes were blocked by incubation overnight in 5% wt/vol dry milk in Tween-Tris-buffered saline (TTBS:
0.5% Tween 20, 30 mM Tris, 150 mM NaCl). Membranes were subsequently
washed three times with TTBS and probed with specific rabbit anti-rat
antibodies: 1-Na+-K+-ATPase,
1-Na+-K+-ATPase, GLUT-2, GLUT-5,
and SGLT-1. The antibodies were diluted in 2% dry milk in TTBS, and
the incubations were done at room temperature.
1- and
1-Na+-K+-ATPase were obtained
from Upstate Biotechnology (Lake Placid, NY).
After incubation in primary antibody, membranes were washed three times
with TTBS. Membranes were then incubated with goat anti-rabbit antibody
conjugated with horseradish peroxidase (Pierce, Rockford, IL). After
three washes in TTBS, the immune complexes were visualized with
SuperSignal chemiluminescent-horseradish peroxidase substrate (Pierce).
After exposure to X-OMAT AR film, the relative band densities were
determined by transmittance densitometry with a Bio-Rad imaging
densitometer (Life Science Group, Cleveland, OH).
Northern immunoblotting.
cDNA probes were produced. Bacteria (Escherichia coli) were
transformed with plasmids containing the desired DNA sequences to be
probed for the Northern blotting. SGLT-1 cDNA probe was donated by Dr.
Davidson, University of Chicago; cDNA probes encoding the
1- and
1-Na+-K+-ATPase subunit isoforms
were obtained from Dr. Lingrel, University of Cincinnati; cDNA probes
encoding GLUT-5 and GLUT-2 were obtained from Dr. Bell, University of
Chicago; ERG probes were obtained from Oncogene Research Products; cDNA
probe encoding proglucagon was obtained form Dr. Fuller, Prince
Henry's Institute of Medical Research, Melbourne; ODC was obtained
from Dr. Blackshear, University of Chicago; and TNF-, IL-2,
IL-6, and IL-10 were obtained from BIO/CAN Scientific. A DIG-labeled
nucleotide (Roche Diagnostics, Laval, Quebec) was incorporated during
the DNA synthesis by using a DNA polymerase (Roche Diagnostics). The
probe concentration was estimated according to comparison with the
intensity of a control prelabeled DNA (Roche Diagnostics).
70°C.
Total RNA was electrophoresed through a denaturing agarose gel (1.16%
agarose) and then transferred from the gel to a nylon membrane by
capillary action overnight. Membranes were then baked at 80°C for
2 h to fix the RNA onto the membrane. As a prehybridization, membranes were incubated for 30 min with DIG easy hybridization solution (Roche Diagnostics). After prehybridization, the labeled probes were hybridized to the corresponding RNA band on the membrane by
incubation with the DIG-labeled probe at the adequate temperature overnight. After stringency washes, membranes were blocked in 1×
blocking solution (10% 10× blocking solution, 90% 1× maleic acid).
The membranes were then incubated with an anti-DIG-alkaline phosphatase
conjugate antibody (Roche Diagnostics).
The detection of the bound antibody was performed by using a CDP-STAR
chemiluminescent substrate (Roche Diagnostics), and membranes were
exposed to films (X-Omat, Kodak) for 10-30 min. The density of the
RNA was determined by transmittance densitometry by using a Bio-Rad
imaging densitometer (Life Science Group).
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RESULTS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal characteristics.
Food intake was similar in the control vehicle and budesonide- and
prednisone-treated animals (Table 1).
Despite this, weight gain was lower (P < 0.05) in the
budesonide than in the prednisone or in the control group. The body
weight gain in rats given 0.75 and 1.0 mg/kg budesonide was similar to
that of controls (data not shown). The percentage of weight gain
(g/day) per food intake (g/day) was lower in the budesonide than in the
control group and was higher in the prednisone than in the control or
budesonide group.
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1 · min1).
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Uptake of sugars.
A curvilinear relationship was noted between the concentration of
D-glucose (4-64 mM) and the rate of glucose uptake
(Fig. 1). The estimated values of
Vmax and of Km for
glucose uptake were unaffected by treatment with prednisone or with
budesonide (0.25 mg/kg) (Table 3).
Budesonide given at a dose of 1.0 mg/kg also had no effect on
D-glucose uptake (data not shown). The jejunal and ileal
rates of uptake of L-glucose and of D-mannitol
were unaffected by prednisone or budesonide, compared with the control group (Table 4).
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1 · min · mM1,
compared with 12.1 nmol · 100 mg
tissue1 · min · mM1
in the control group (Table 5).
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Transporter protein abundance and expression of mRNA.
In animals given prednisone, the SGLT-1 abundance was reduced
(P < 0.05) in the jejunum compared with that in the
control group and did not change in the ileum (Table
6). Budesonide did not affect the
abundance of SGLT-1. The Na+-K+-ATPase
1 was not changed in either the jejunum or ileum (Table 6). No changes in Na+-K+-ATPase
1 abundance were observed in the jejunum. However, the Na+-K+-ATPase 1 abundance was
reduced in the ileum of animals given prednisone, compared with animals
given control vehicle or given budesonide. Steroids had no effect on
GLUT-5 and GLUT-2 abundance in the jejunum or ileum.
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1, or
Na+-K+-ATPase 1 were observed in
the jejunum and ileum of animals given budesonide or prednisone,
compared with the control group (Table 7). Steroids had no effect on GLUT-5 or
GLUT-2 mRNA expression in the jejunum or ileum.
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ERG, proglucagon, and ODC mRNA expression.
No detectable signal was observed for c-fos. Steroids had no
effect on the expression of c-myc and c-jun
(Table 8). Steroids had no effect on
proglucagon mRNA expression at either site. In the ileum but not in the
jejunum of animals given prednisone, the ODC mRNA expression was
increased compared with that of animals in the control group or those
given budesonide.
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Cytokine gene expression.
Steroids had no effect on the mRNA expression of TNF-, IL-2, IL-6,
or IL-10 in either the jejunum or ileum (Table
9).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals fed budesonide had a reduced rate of weight gain that was not explained by a lower food intake or by a lower rate of intestinal uptake of glucose or fructose. In fact, animals given budesonide had increased uptake of fructose (Table 5). The mechanism responsible for this lower weight gain in rats given budesonide was not established in this study. However, it is possible that the effect of budesonide on weight gain may have been spurious: first, because, at higher doses (0.75 and 1.0 mg/kg), weight gain was similar to that of controls; and second, because budesonide (0.25 mg/kg) had no effect on body weight gain in animals fed a semisynthetic diet enriched with saturated or polyunsaturated fatty acids (unpublished observations). It is interesting to note that the dose of prednisone used in this study did not alter food intake or body weight gain, despite its systemic nature.
Prednisone acts systemically on the intestine, in contrast to the largely local action of budesonide (1). In adult animals, prednisone (in a dose of 0.75 mg/kg for 28 days) increases glucose absorption (16). The lack of effect of prednisone on glucose uptake in this study may be due to the younger age of the animals. Other functions of the intestine have been shown to change with the administration of steroids, and the time or age of the animals is critical. For instance, starting dexamethasone on the 16th day produces an accelerated rise in sucrase-isomaltase and sucrase-isomaltase mRNA, but starting on the 18th day did not have an effect (50). The lack of effect of prednisone or budesonide on the jejunal or ileal uptake of L-glucose or D-mannitol (Table 4) suggests that the passive paracellular contribution to sugar uptake is also unaffected by these steroids. The lack of effect of either prednisone or budesonide on the value of the Vmax of glucose uptake in these 4-wk postweanling rats (Table 3) suggests that there was no change in the activity of the SGLT-1 in the BBM. The reduced jejunal abundance on SGLT-1 in animals given prednisone (Table 6) did not affect the activity of the transporter. This suggests that, under some conditions, there may be a dissociation between SGLT-1 protein abundance and transporter activity.
The linear relationship between fructose uptake and concentration (over the range used in this study) precluded the calculation of values for Vmax or Km. Fructose uptake is mediated by GLUT-5 (the sodium-independent fructose transporter in the BBM). In this study, the increased fructose uptake with budesonide or prednisone was not associated with enhancement in the abundance of GLUT-5 protein or expression of GLUT-5 mRNA. This suggests that the increase in fructose uptake observed with steroids is due to posttranslational control of GLUT-5. Another possibility would involve the distribution of GLUT-5 along the crypt-villus unit that could be altered without changes in the total abundance of GLUT-5, as measured by Western blotting (52). GLUT-2 transports fructose across the BLM, and recent evidence suggests that GLUT-2 may also be in the BBM (28-30). However, no changes in GLUT-2 protein abundance or mRNA expression were observed, so that it is unlikely that the increased fructose uptake observed with steroids could be explained by enhanced transport of this sugar out of the enterocyte.
Steroids have been suggested to increase the expression of a series of transcription factors (51, 53-55). ERG such as c-myc, c-jun, and c-fos have been demonstrated to be involved in processes of proliferation and differentiation, as well as ODC, a key enzyme in the synthesis of polyamines and a requirement in any proliferative event (34-37). Proglucagon has been shown to be involved in the intestinal adaptive process (31, 32, 37). For example, short-chain fatty acids increase the ileal c-myc and proglucagon expression in rats undergoing intestinal resection (37). The finding in this study of increased ileal ODC mRNA with prednisone (Table 8) may explain part of the enhanced fructose uptake with this steroid, but does not explain the enhancing effects of budesonide on fructose uptake. ODC may be responsible for the increased uptake of D-fructose in animals given prednisone. By a mechanism probably involving proliferative events, ODC might be able to induce transporters such as GLUT-5 and, consequently, absorption. Clearly, there must be other signals responsible for the adaptive effect of steroids on intestinal fructose uptake.
The major factor for the understanding of the absence of changes in the expression of ERG comes from the fact that major changes observed in previous studies occur in the first 24 h after the stimuli (37). We have looked only after 2 wk of steroid administration, because we wanted to assess the chronic effect of steroids on ERG expression. Therefore, initial increases in ERG may in fact have occurred, and ERG may be of physiological and pathological importance at the early stage after the administration of steroids, rather than after later administration, as was the case in this study.
The administration of IL-6, IL-1, and IL-8 has been shown to
increase the uptake of glucose in in vitro studies (42).
It was hypothesized that changes in cytokine expression might be responsible for the phenotypic alterations in transport activity and
absorption acting by intracellular signaling mechanisms that would
result in expression of transporters (41-43).
However, cytokine signaling was not observed with either prednisone or
budesonide. Therefore, the effect of steroids on the fructose uptake
was not explained by alterations in the mRNA expression of
TNF-, IL-2, IL-6, and IL-10.
In summary, 1) giving postweaning rats 4 wk of budesonide or prednisone in doses equivalent to those used in clinical practice increases fructose but not glucose uptake; and 2) the enhanced uptake of fructose was likely regulated by posttranscriptional events.
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ACKNOWLEDGEMENTS |
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The authors thank Kim Doring, Rob Drummond, and Elizabeth Wierzbicki for technical assistance.
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FOOTNOTES |
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The financial support of the Natural Sciences and Engineering Research Council of Canada, Medical Research Council (MRC) of Canada, and AstraZeneca Canada (former Astra Pharma) with an MRC/Pharmaceutical Manufacturers Association of Canada grant was greatly appreciated. We also thank Ciencia Laboratorio Medico and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior for the support of A. Thiesen. G. E. Wild is a research scholar of Fonds de la Recherche en Santé du Québec.
Address for reprint requests and other correspondence: A. B. R. Thomson, 519 Robert Newton Research Bldg., Univ. of Alberta, Edmonton, Alberta, Canada T6G 2C2 (E-mail: alan.thomson{at}ualberta.ca).
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 September 13, 2002;10.1152/japplphysiol.00134.2002
Received 21 February 2002; accepted in final form 10 September 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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