Departments of Molecular Medicine and Woman and Child Health, Karolinska Institute, Karolinska Hospital, 171 76 Stockholm, Sweden; and Institute of Pharmacology and Therapeutics, Faculty of Medicine, 4200 Porto, Portugal
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ABSTRACT |
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During high-salt diet endogenous dopamine (DA)
reduces jejunal sodium transport in young but not in adult rats. This
study was designed to evaluate whether this effect is mediated, at the cellular level, by inhibition of
Na+-K+-ATPase
activity. Enzyme activity was determined in isolated jejunal cells by
the rate of
[-32P]ATP
hydrolysis. Cells were obtained from weanling and adult rats fed either
with high- or normal-salt diet. In 20-day-old but not in 40-day-old
rats
Na+-K+-ATPase
activity was significantly reduced during high-salt diet. This
inhibition was abolished by a blocker of DA synthesis. The decreased
activity was associated with a decreased
1-subunit at the plasma
membrane. During high-salt diet there was an increase in DA content in
jejunal cells from 20-day-old rats, associated with a parallel decrease
in 5-hydroxytryptamine, compared with normal-salt diet. In 40-day-old
rats, however, the catecholamine level remained unchanged during
high-salt diet. Incubation of isolated jejunal cells with DA resulted
in a dose-dependent inhibition of
Na+-K+-ATPase
activity in 20- but not in 40-day-old rats. We conclude that during
high-salt diet, jejunal
Na+-K+-ATPase
in 20-day-old rats is inhibited, and this effect is likely to be
mediated by locally formed DA.
sodium-potassium-adenosinetriphosphatase synthesis; serotonin; L-3,4-dihydroxyphenylalanine
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INTRODUCTION |
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WE HAVE RECENTLY SHOWN that sodium absorption and catecholamine content in the jejunal mucosa of young rats were higher than in mature animals (14). In addition, young animals during high-salt diet experienced a decrease in sodium absorption with a parallel increase in tissue levels of dopamine (DA), whereas in adult animals there were no significant changes in sodium absorption, nor in catecholamine content of the jejunal mucosa (6, 14). That study suggested that during high-salt diet, an increase in the jejunal levels of DA associated with a decrease in the norepinephrine (NE) content was responsible for the control of sodium absorption in the jejunal mucosa of young animals. Adult (40-day-old) animals did not have a significant change in jejunal sodium absorption or in catecholamines levels during high-salt diet. The lack of any change in the jejunal function in response to high-salt diet coincided with the period in which the renal function has reached maturation (23, 24), thus suggesting complementary functions between the intestine and the kidney during development.
Sodium and water homeostasis is a critical step during adaptation to early life; although nephrogenesis is completed at birth, renal tubular function continues to develop postnatally (23, 24). During early postnatal life the kidney has a limited capacity to regulate fluids and electrolyte homeostasis, leading to high sodium excretion and often to negative sodium balance and hyponatremia (30, 31). Intestinal function is also determined by a developmental process that has a great impact not only during the uptake of nutrients but, equally importantly, in maintaining electrolytes and water metabolism (17, 32). Therefore, understanding the cellular mechanisms controlling this process is of paramount importance.
In transporting epithelia, vectorial movement of sodium is accomplished by means of the Na+-K+-ATPase located at the basolateral plasma membrane and several sodium transport mechanisms localized at the apical domain of the cell (25). In the renal epithelia (proximal and distal tubules) of mature animals, DA decreases Na+-K+-ATPase activity during high-salt diet, which is believed to contribute to increased urinary sodium excretion (3). Thus the present study was designed to investigate whether DA-dependent inhibition of sodium absorption across the jejunal mucosa of young animals is associated with decreased Na+-K+-ATPase activity.
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EXPERIMENTAL PROCEDURES |
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All experiments were performed in Sprague-Dawley rats (BK Universal, Sollentuna, Sweden), aged 20 (weaning) and 40 (adult) days, weighing 37.1 ± 1.2 g (n = 8) and 170 ± 3.4 g (n = 8), respectively. Animals were kept in air-conditioned animal quarters, in litters of four animals per litter. Adult rats were fed ordinary solid rat chow (BK Universal); young rats were given the same chow but softened by mixing it with water. Tap water was provided ad libitum. The high-salt diet group received as drinking fluid 0.9% saline instead of tap water. The 20-day-old rats on high-salt diet were given saline for 4 days, whereas the 40-day-old rats received saline for 7 days before the study. We have previously examined Na+-K+-ATPase activity in response to high salt (3, 20) and found no differences between 2 and 7 days of administration of high-salt diet. The daily sodium intake averaged 0.5 and 5.0 mmol/100 g body wt in normal- and high-salt diet groups, respectively.
To determine the role of endogenous DA, rats were injected intraperitoneally (0.1 ml) with benserazide (10 mg/kg body wt; Roche, Basel, Switzerland), an inhibitor of aromatic L-amino acid decarboxylase (AADC), 1 h before the animals were killed. This treatment was sufficient to cause complete inhibition of the peripheral DA-converting enzyme for up to 4 h after administration (10). Control animals were injected with the same volume of vehicle (sterile water).
Cell isolation. The method for cell isolation was as described previously (18, 22) with minor modifications. Briefly, the animals were killed by decapitation under anesthesia, and the abdominal cavity was immediately opened to excise a jejunal segment ~10 cm in length. The selected segment was placed on an ice-cold glass plate, cut in smaller segments of ~1.5 cm in length, and rinsed free from blood and intestinal contents with saline (0.9% NaCl). The tissue fragments were everted with fine forceps and incubated for 45 min in 5 ml warm (37°C) and gassed (95% O2-5% CO2) Hanks' solution with 0.06% collagenase type I (Sigma Chemical, St. Louis, MO). At the end of the incubation period the preparation was gently vortexed to allow the epithelial cells to detach. The fragments were then removed from the solution, and the medium containing the detached cells was centrifuged (200 g, 4°C) for 4 min. The cell pellet formed was resuspended in Hanks' solution. Cell viability was estimated by the trypan blue (0.04%, 1 min) exclusion method, and the percentage of viable cells (excluding the dye) was >90%, as determined by hemocytometer counting.
Determination of
Na+-K+-ATPase
activity.
Na+-K+-ATPase
activity in isolated cells in suspension was determined as described
previously (2). Briefly, after cell isolation 10-µl aliquots (protein
content ~5-15 µg protein) were transferred to the
Na+-K+-ATPase
assay medium (final volume 100 µl) containing (in mM) 50 NaCl, 5 KCl,
10 MgCl2, 1 EGTA, 50 Tris-HCl, 10 Na2ATP (Sigma), and
[32P]ATP (Amersham;
specific activity 3,000 Ci/mmol) in tracer amounts (3.3 nCi/µl).
Cells were transiently exposed to a thermic shock (10 min at
20°C) to render the plasma membrane permeable to ATP. The
samples were then incubated at 37°C for 15 min. The reaction was
terminated by rapid cooling to 4°C and addition of TCA-charcoal (5-10%). After the charcoal phase was separated (centrifugation at 14,000 rpm for 5 min), an aliquot from the supernatant was taken and
the liberated 32P was counted.
Na+-K+-ATPase
activity was calculated as the difference between test samples (total
ATPase activity) and samples assayed in a medium devoid of
Na+ and
K+ and in the presence of 2 mM
ouabain (ouabain-insensitive ATPase activity). Protein
determination was performed according to Bradford using a conventional
dye reagent (Bio-Rad, Richmond, CA).
Assay of tissue catecholamines.
Segments of jejunum were opened longitudinally with fine scissors,
rinsed free from blood and intestinal contents with cold saline (0.9%
NaCl), and the jejunal mucosa was removed with a scalpel. The mucosae
thus removed were blotted onto filter paper, weighed, placed in 1 ml
0.2 M perchloric acid, and stored frozen at 20°C. The assay
of L-3,4-dihydroxyphenylalanine
(L-DOPA), NE, DA, and
5-hydroxytryptamine (5-HT) was performed by means of HPLC with
electrochemical detection (EC) as previously described (13). Briefly,
aliquots of 500 µl of perchloric acid in which the tissue had been
kept were placed in 5-ml conical-based glass vials with 50 mg alumina,
and the pH of the sample was immediately adjusted to 8.6 by addition of
Tris buffer. Mechanical shaking for 10 min was followed by
centrifugation, and the supernatant was discarded. The adsorbed
catecholamines were then eluted from the alumina with 200 µl of 0.2 M
perchloric acid on Spin-X microfilter tubes (Costar, Badhoevedorp, The
Netherlands); 50 µl of the eluate were injected into an HPLC-EC
system. The detection was performed electrochemically by means of a
thin-layer cell with a glassy carbon working electrode, an Ag/AgCl
reference electrode, and an amperometric detector (Gilson model 141;
Gilson Medical Electronics, Villiers Le Bel, France). The detector cell
was operated at 0.75 V. The current produced was monitored using the
Gilson 712 HPLC integration software connected to a personal computer
system. The mobile phase was a degassed solution of 0.1 mmol/l citric acid, 0.5 mmol/l sodium octyl sulfate, 0.1 mol/l sodium
acetate, 0.17 mmol/l ethylenediaminetetraacetic acid, 1 mmol/l
dibutylamine, 12% methanol (vol/vol), pH 3.5, which was pumped at a
rate of 1.0 ml/min. Standard solutions of
L-DOPA, NE, DA, 5-HT, and
dihydroxybenzylamine (internal standard) were injected at different
concentrations, and peak height increased linearly. The lower limits
for detection of L-DOPA, NE, DA,
and 5-HT ranged from 350 to 500 fmol.
Western blot analysis.
Jejunal cells were isolated from 20- and 40-day-old rats as previously
described. The cells were homogenized, and aliquots (50 µg protein)
were analyzed by SDS-PAGE using the Laemmli buffer system as described
(1). Proteins were transferred to polyvinylidene difluoride membranes
(Immobilon-P, Millipore, Bedford, MA) in a buffer containing 25 mM
Tris-HCl, 192 mM glycine, SDS, 0.1% (wt/vol), and 20% methanol
(vol/vol). Transferring was performed at 1 Amper during 3 h using a
Transphor system (Hoaffer, San Francisco, CA). Protein identification
was carried out using a monoclonal antibody against the
1-subunit (21; courtesy of Dr.
M. Caplan) and the
2 and
3 with a monoclonal antibody
kindly provided by Dr. K. J. Sweadner. Immunoreactivity was detected
with an enhanced chemiluminescence detection kit (Amersham) used
exactly as recommended by the manufacturer. Measurements
were performed with multiple exposures to ensure that signals were
within the linear range of the film. Scans were performed using a Scan
Jet IIc scanner (Hewlett-Packard, Palo Alto, CA). Each band was scanned
two times in different regions, the scans were averaged, and the area
of the peak minus the background (in arbitrary units) was quantified.
Statistical analysis. The data were analyzed using Student's t-test. Values are means ± SE. P < 0.05 was considered significant. A significant difference between one control and two experimental groups was determined using ANOVA with the Newman-Keuls posttest method (29)
The accumulation of L-DOPA in the jejunal mucosa after inhibition of AADC was calculated from a semilog plot of L-DOPA levels against time of inhibition; the slope of accumulation was calculated using linear regression. The fractional accumulation of L-DOPA (k) was then obtained from the expression k = slope/0.434 (6). ![]() |
RESULTS |
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Na+-K+-ATPase
activity was determined in isolated jejunal cells from 20- and
40-day-old rats. Basal enzyme activity, examined under optimal (maximal
velocity) substrate conditions, was 300 ± 85 (n = 8) and 526 ± 51 (n = 5) nmol
Pi · mg
protein1 · min
1,
respectively. Administration of the high-salt diet resulted in a
significant decrease in
Na+-K+-ATPase
activity in 20- but not 40-day-old rats (Fig.
1). This decrease in 20-day-old rat
Na+-K+-ATPase
activity observed during high-salt diet was blunted when benserazide,
an inhibitor of AADC, was given 1 h before the
experiments.
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The presence of different
Na+-K+-ATPase
isoforms in the jejunal cells has not been previously characterized.
Thus we first determined which of the isoforms are present in jejunal
cells from 20- and 40-day-old rats (Fig. 2)
and whether this pattern was affected by high-salt diet. Isolated rat
striatum was used as a positive control. Whereas all three isoforms
were present in the striatal membranes, the jejunal cell plasma
membrane exhibited the presence of only the
Na+-K+-ATPase
1-isoform (Fig. 2). In
addition, plasma membranes isolated from jejunal cells from 20-day-old
rats on high-salt diet showed a significant reduction (% of control
74.2 ± 4.8, n = 4) in the
1-subunit abundance compared
with age-matched controls receiving normal saline, whereas in
40-day-old animals high salt did not affect the
1-subunit abundance.
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Levels of L-DOPA, NE, DA, and 5-HT were determined in the jejunal mucosa of 20- and 40-day-old rats fed normal- and high-salt diets. Basal levels of all monoamines in the jejunal mucosa of 20-day-old rats were higher than in 40-day-old rats (Table 1), in agreement with results reported in a previous study (14). In 20-day-old rats administration of high-salt diet resulted in a significant increase (~57%) in the tissue level of DA, whereas 5-HT content was significantly decreased by ~27% (Fig. 3). The tissue content of NE did not change, regardless of the diet administered. Benserazide treatment induced a significant (P < 0.05) increase in L-DOPA (from 113 ± 18.8 to 752 ± 165 pmol/g) and abolished the increase in DA during high-salt diet (Fig. 3, left) but did not induce a significant change in the tissue levels of 5-HT (Fig. 3, right). In 40-day-old rats high-salt diet did not significantly affect the levels of either DA or 5-HT (Fig. 4). During inhibition of AADC with benserazide (Fig. 5), the rate constant of accumulation of L-DOPA in the jejunal mucosa of young rats (k = 0.0288 ± 0.0030, n = 6) was found to be similar (P = 0.09) to that observed in adult rats (k = 0.0356 ± 0.0021, n = 7); the total amount of L-DOPA accumulated during AADC inhibition was, however, considerably higher in young rats (932 ± 39 pmol/g) than in adult rats (220 ± 33 pmol/g).
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We next examined the possibility that DA may affect fluid transport across the intestinal epithelium by inhibiting the Na+-K+-ATPase activity. In isolated cells from 20-day-old animals, in vitro incubation with DA resulted in a concentration-dependent inhibition of Na+-K+-ATPase activity (Fig. 6). The EC50 for DA-induced inhibition of Na+-K+-ATPase was ~100 nM. DA (1 µM) failed to inhibit Na+-K+-ATPase activity in isolated cells from 40-day-old rats (% of control 93.1 ± 3.8, n = 7, not significant).
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Because the high-salt diet was not only associated with increased DA levels but also with a decrease in the cellular content of 5-HT, it was next evaluated whether the inhibitory action of DA was affected by 5-HT (Fig. 7). The inhibitory effect of DA was prevented by 1 and 10 µM 5-HT.
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DISCUSSION |
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High-salt diet in young animals is associated with a decrease in sodium and water absorption in the small intestine (14). The results presented here suggest that at the cellular level the decreased sodium absorption (vectorial transport) could be the result of decreased Na+-K+-ATPase activity. Moreover, control of the Na+-K+-ATPase catalytic activity is likely to be dependent on endogenous DA tissue levels.
Tissue catecholamines are important regulators of jejunal cell function (7). In a previous report we have demonstrated that the ability of young animals to maintain sodium balance during high-salt diet depends on the tissue levels of DA (14). Their ability to reduce sodium and water absorption during high-salt diet is blunted by benserazide (14). The data presented here suggest that the effect of DA could be mediated by inhibition of Na+-K+-ATPase activity. Young rats on a high-salt diet [transport less sodium across the jejunal epithelium (14)] demonstrate lower Na+-K+-ATPase activity and higher DA tissue levels than young animals on normal-salt diet. The reduction in Na+-K+-ATPase activity during high-salt diet could be prevented by pretreatment with benserazide, an inhibitor of DA synthesis, suggesting a causal relationship between endogenous DA and inhibition of the sodium pump. The possibility that DA may regulate Na+-K+-ATPase activity was further supported by experiments demonstrating that enzyme activity was reduced in jejunal cells incubated in vitro with DA and that this effect was only present in jejunal cells isolated from young but not adult rats. The finding that exogenous DA produced an effective inhibition on Na+-K+-ATPase activity in isolated cells from the jejunal mucosa is an additional argument favoring the view that inhibition of intestinal sodium absorption by DA may be dependent on an interaction with the enzyme.
At the cellular level inhibition of
Na+-K+-ATPase
activity by DA could be the result of a reduced number of pump units in
the plasma membrane, a mechanism perhaps analogous to the one present in renal epithelial cells (8, 9). This view is supported by the finding
that plasma membranes isolated from jejunal cells of young rats on a
high-salt diet showed a parallel decrease in the
Na+-K+-ATPase
1-subunit abundance compared
with age-matched rats on a normal-salt diet.
Na+-K+-ATPase activity was determined under optimum substrate concentrations (sodium, potassium, and ATP), thus excluding the possibility that the inhibitory effect of DA could be secondary to changes in sodium permeability. However, the latter does not exclude the possibility that during in vivo conditions there also exists a concomitant decrease in apical sodium permeability, as reported for the renal epithelia (4, 5); a simultaneous decrease in apical sodium permeability and Na+-K+-ATPase activity would result in decreased vectorial transport without changes in intracellular sodium.
In contrast to data obtained from young rats, adult rats were found to
show higher
Na+-K+-ATPase
activity. In addition, contrariwise to young rats, changes in neither
Na+-K+-ATPase
activity nor
Na+-K+-ATPase
1-subunit abundance were found
to occur in adult rats during a high-salt diet. Following the rationale
used for young animals that associates sodium load,
Na+-K+-ATPase
activity, and DA levels, it might be suggested that
Na+-K+-ATPase
activity in adult rats behaved differently because jejunal cells have
less ability to synthesize DA and are less sensitive to the amine;
altogether, this would result in a decreased dopaminergic tonus on the
sodium pump. Several observations point in this direction. First, the
basal levels of DA and L-DOPA,
the amine precursor, in adult rats were one-half those in young rats.
Second, exogenous DA failed to produce inhibition of
Na+-K+-ATPase
in jejunal cells of adult rats. This, however, does not explain why
adult rats behave differently from young rats when challenged with a
high-salt diet. Despite low levels of endogenous L-DOPA and DA in the jejunal
mucosa of adult rats during normal-salt diet, the rate of
L-DOPA utilization (given from
the L-DOPA/DA ratios) was
similar to that observed in young rats. This contrasts with the results
obtained during high-salt diet, in which the rate of
L-DOPA utilization in young
animals was higher than in adult animals (Table
2). It appears therefore that during
high-salt diet, the link between the stimulus (high-sodium intake) and
the ability of the jejunal cells to increase DA synthesis is not
present at an older age. However, this reduced ability of adult rats to synthesise DA may not be related to a decrease in AADC activity, because after being challenged with benserazide the rate of
accumulation of L-DOPA is
similar in both groups of animals (Fig. 5, see also Ref. 6).
This may indicate that the decreased ability to synthesize DA during
high-salt diet is related to a reduced availability of
L-DOPA to the intracellular
milieu and therefore to AADC. The cellular uptake of
L-DOPA, at least in renal
tubular epithelial cells, has an important sodium-dependent component
(26), and a possible explanation for this reduced ability of adult rats to synthesize DA could reside in the appearance of resistance to
sodium-dependent mechanisms as animals become older. Although one may
attribute the failure of adult animals to inhibit
Na+-K+-ATPase
activity to decreased ability to synthesize DA, it is interesting to
note that in young animals the jejunal content of
L-DOPA was higher than in adult
animals despite the fact that they received a similar diet. On the
other hand, the finding that exogenous DA is devoid of an inhibitory
effect on
Na+-K+-ATPase
activity in adult rats may suggest a developmental change in the
response that coincides with the maturation of the renal function and
furthermore with the ability of DA to inhibit
Na+-K+-ATPase
activity in renal epithelial cells (15).
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Another aspect of importance concerns the role of 5-HT, by far the most abundant amine at the level of the intestinal epithelia and a well-known intestinal secretagogue (9, 18). Although there are differences between species and between different areas of the digestive tract (jejunum, ileum, and colon), the main effect of 5-HT is a potent stimulation of intestine fluid and electrolyte secretion. This appears to result from an increase in the electrogenic secretion of chloride ions together with an inhibition of electroneutral absorption of sodium chloride (16, 33). The finding that high-salt diet in 20-day-old rats was associated with a decrease in 5-HT levels and Na+-K+-ATPase activity, and because in rat renal tubules 5-HT was found to stimulate the sodium pump (27, 28), it was hypothesised that at the intestinal level an association between 5-HT levels and Na+-K+-ATPase activity could also be present. However, the decrease in Na+-K+-ATPase activity during high-salt diet was abolished by benserazide, and the levels of 5-HT were not even modified. This only suggests that 5-HT, in contrast to DA, resides in a storage compartment (enterochromaffin cells; 12), which is fairly stable and not so easily modified by the acute administration of benserazide. As mentioned previously, in the kidney 5-HT was found to stimulate Na+-K+-ATPase activity, and the coincubation of 5-HT agonist with DA was found to revert the inhibitory effect of the latter (27). In the present study, the inhibitory action of maximal doses of DA on Na+-K+-ATPase activity was significantly prevented by coincubation with 5-HT, suggesting the presence of a functional antagonism between the two amines in the control of enzyme activity. To our knowledge this is the first time that 5-HT in the intestine is described to exert an effect on Na+-K+-ATPase. It is therefore difficult to integrate this information with the evidence that 5-HT decreases net sodium absorption and stimulates net chloride secretion, which necessarily needs further study.
In conclusion, the results of this study indicate that the reduced sodium absorption observed in young rats during high-salt diet is probably due to decreased Na+-K+-ATPase activity. This study also demonstrated that the rate of utilization of L-DOPA in jejunal cells of adults rats on high-salt diet is lower than in young rats, and this may be due to a decreased availability of the substrate to the intracellular milieu rather than a specific deficiency in AADC activity.
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ACKNOWLEDGEMENTS |
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We are grateful to Dr. Adrian I. Katz for fruitful discussions and constructive criticisms.
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FOOTNOTES |
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This study was supported by grants from the Swedish Medical Research Council (A. M. Bertorello), and Fundação para Ciência e a Tecnologia (P. S. Silva). M. A. Vieira-Coelho and V. A. Lucas Teixeira are recipients of Praxis 21 Fellowships.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: A. M. Bertorello, Karolinska Hospital, Rolf Luft Center for Diabetes Research L6B:01, 171 76 Stockholm, Sweden.
Received 19 February 1998; accepted in final form 12 August 1998.
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