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Experimental Physiology 89.6 pp 753-765
DOI: 10.1113/expphysiol.2004.028621
© The Physiological Society 2004
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Excretion of electrolytes in Brown Norway and Fischer 344 rats: effects of adrenalectomy and of mineralocorticoid and glucocorticoid receptor ligands

Nathalie Marissal-Arvy1 and Pierre Mormède1

1 Neurogénétique et Stress, INSERM U471 - INRA UMR1243 - Université de Bordeaux 2, Institut François Magendie de Neurosciences, 1, rue Camille Saint Saëns, 33077 Bordeaux Cedex, France


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Our previous studies showed that adrenalectomy (ADX) has surprisingly no effect on body weight and fluid intake in the Brown Norway rat strain, suggesting that mineralocorticoid receptor (MR)-mediated effects are present even in absence of corticosteroids in this strain. Moreover, glucocorticoid receptor (GR)-mediated mechanisms are more effective in Brown Norway than in Fischer 344 rats. Such functional differences in corticosteroid receptor pathways between Brown Norway and Fischer 344 rats led us to compare the effect of ADX and MR/GR-mediated actions on sodium and potassium excretion between these two rat strains. To this end, we first measured the effect of an acute high dose of aldosterone on the urinary Na+/K+ concentration ratio in intact and ADX Brown Norway and Fischer 344 rats. Second, to discriminate mineralocorticoid from glucocorticoid actions, we treated chronically ADX rats with increasing doses of aldosterone or RU28362, a pure GR agonist, in the drinking fluid. As sodium homeostasis involves salt appetite regulation, behaviour under mineralocorticoid control, we also measured saline preference in Brown Norway and Fischer 344 rats. Our data illustrate: (1) the very limited effect of ADX on body weight, food and fluid intake, diuresis, natriuresis, kaliuresis and salt appetite in Brown Norway rats, supporting the presence of MR signalling pathways in the absence of adrenal steroids in these rats; (2) the insensitivity of MR to aldosterone in intact Brown Norway rats, and the reduced sensitivity of MR to aldosterone in ADX Brown Norway rats compared with ADX Fischer 344 rats; and (3) the greater sensitivity of GR-related mechanisms to RU28362 in Brown Norway than in Fischer 344 rats in terms of body weight gain and electrolyte excretion. Considering that both MRs and GRs regulate hypothalamic–pituitary–adrenal axis processes, such functional differences in corticosteroid receptors could be at the origin, at least partly, of the strain differences in corticotropic activity/reactivity to stress previously described.

(Received 8 July 2004; accepted after revision 9 September 2004; first published online 13 September 2004)
Corresponding author Nathalie Marissal-Arvy: INSERM U471 - INRA UMR1243 - Université de Bordeaux 2, Institut François Magendie de Neurosciences, 1, rue Camille Saint Saëns, 33077 Bordeaux Cedex, France. Email: marissal{at}bordeaux.inserm.fr


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Electrolyte homeostasis determines extracellular fluid volume stability and maintenance of blood pressure (Ortiz & Garvin, 2001), and the slightest imbalance can cause disease (Funder et al. 1990; Boon et al. 1997). Aldosterone was the first hormone shown to be involved in the regulation of sodium and potassium balance (Bhargava et al. 2004). A deficit of aldosterone action leads to sodium wasting and hyperkalaemia, whereas mineralocorticoid excess provokes sodium retention and is a well-known cause of hypertension in humans (Booth et al. 2002; Bravo, 2003) and rats (Funder, 2002). The regulation by aldosterone is achieved by adjusting the transport rate of electrolytes across the epithelia lining the distal parts of excretory systems (distal nephron and colon, excretory glands) where both mineralocorticoid and glucocorticoid receptors (MRs and GRs) are present (Todd-Turla et al. 1993). Because aldosterone and corticosterone bind to the MR with the same affinity (Kd < 1 nM), the specificity of aldosterone for MRs in peripheral target tissues is in part ensured by the activity of the enzyme 11ß-hydroxysteroid dehydrogenase 2 which inactivates endogenous glucocorticoids (Bonvalet, 1998; Farman & Rafestin-Oblin, 2001). Even though the kaliuretic effect of the two types of corticosteroid receptors is nowadays largely accepted, GR effects on natriuresis remain much debated (Funder et al. 1990; Muller et al. 2003). However, most old (Teutsch et al. 1981; Campen et al. 1983; Kenyon et al. 1984; Stewart et al. 1988) and recent (Muller et al. 2003) in vivo studies in rat show that GR-specific agonists such as dexamethasone or RU28362 increase sodium excretion.

MRs and GRs have also been involved in the control of hypothalamic–pituitary–adrenal axis activity and reactivity to stress (Dallman et al. 1994). In the present work, we focused on two inbred rat strains, Brown Norway and Fischer 344, shown to display different profiles of corticosterone secretion in basal condition or in response to a restraint stress (Sarrieau & Mormède, 1998; Sarrieau et al. 1998). In two previous studies (Marissal-Arvy et al. 1999, 2000), we showed that adrenalectomy (ADX) had no effect on food and fluid intake in Brown Norway rats, suggesting that MR signalling pathways are present even in absence of corticosteroids in this strain. On the other hand, body weight, plasma transcortin and thymus weight were reduced to a greater extent in Brown Norway than in Fischer ADX rats, when treated chronically with RU28362, suggesting a greater efficacy of GR-mediated mechanisms in Brown Norway rats. Such functional differences in corticosteroid receptors between Brown Norway and Fischer 344 rats led us to investigate the effect of ADX and MR/GR-mediated actions on sodium and potassium excretion in these two rat strains (experiment 1). As sodium homeostasis includes salt appetite regulation (Stellar & Epstein, 1991), a behaviour under mineralocorticoid control (Pietranera et al. 2001), we also measured saline preference in Brown Norway and Fischer 344 rats (experiment 2).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Animals

Male inbred Fischer 344 and Brown Norway rats, 5 weeks old and weighing 100–140 g, were purchased from IFFA Credo (L'Arbresle, France). They were housed in a temperature-controlled room (23 ± 1°C) with a 12 h light–12 h dark cycle (lights on at 07.00 h). Food (A04, Scientific Animal Food & Engineering, Villemoisson-sur-Orge, France, 2.9 kcal g–1, 2.5 g of salt per 100 g of chow) and tap water (experiment 1) or 0.45–2.7% saline (experiment 2) were provided ad libitum. All rats were allowed to adapt to the animal room for 10 days before the start of experiments, and placed in individual metabolism cages 1 week before surgery to familiarize them with this environment and the handling procedures. Bilateral ADX (21 rats per strain, in two successive replications) was performed under pentobarbital anaesthesia (0.1 ml (100 g body weight)–1). Sham-operated animals (10 rats per strain, in two successive replications) were submitted to anaesthesia and bilateral laparotomy. Incisions were closed with surgical gut and wound clips.

Body weight, food and fluid intake (by weighing the bottles) and urine production were measured daily. Urine was centrifuged (4500 g, 15 min, 4°C), and a 5-fold diluted aliquot of the daily urine samples was stored at –80°C for later analysis of Na+ and K+ concentrations and osmolarity.

Excretion of Na+ and K+ (experiment 1)

In 1957, Kagawa et al. first published details of a bioassay, where the mineralocorticoid activity of a test substance is gauged by its ability to alter the urinary [Na+]/[K+] ratio of ADX rats. In order to test the functional properties of the Brown Norway rat MR, we first measured the effect of an acute high dose of aldosterone on the urinary [Na+]/[K+] ratio in intact and ADX Brown Norway and Fischer 344 rats. In the second part, in order to discriminate mineralocorticoid from glucocorticoid actions, and to test functional differences in corticosteroid receptors between Brown Norway and Fischer 344 rats, we treated ADX rats with increasing doses of aldosterone and RU28362. To study electrolyte excretion without any Na+ load, rats were kept on tap water rather than saline, as reported by Sonnenberg (1977). The experimental design is shown in Fig. 1.



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  		Figure 1.  Experimental design
Dotted lines represent ADX rats. Di refers to the ith day after ADX. Concentrations of ligand in drinking water are shown under time lines, each 4-day treatment being separated from the next by a 3-day washout period (WO).

 
Control measurements, ADX and acute administrations of aldosterone.  During this period, nine measurements were made in intact rats and 11 measurements after surgery. After 5 days of acclimation to metabolism cages, half of the rats were injected with an acute high dose of aldosterone, which has previously been shown to induce a large decrease of the [Na+]/[K+] ratio 6–8 h after injection (Campen et al. 1983; Burton et al. 1995; Kim et al. 1998). Aldosterone (100 µg (100 g body weight)–1) was injected subcutaneously. Control rats received corresponding amounts of vehicle. A water load (3 ml) was administered intraperitoneally to all rats. Urine was collected for 8 h after injection as previously described (Uete & Venning, 1962). Four days later, two-thirds of the rats were ADX.

In a preliminary study with Wistar rats, we showed that the urinary [Na+]/[K+] ratio was markedly increased by ADX, with a peak on the third day (D3), and returned to the sham values by the seventh day after surgery. In order to prevent the peak of urinary [Na+]/[K+] ratio induced by ADX, and to compare MR mechanisms between Brown Norway and Fischer 344 rats after ADX, half of the ADX rats were injected with aldosterone (100 µg (100 g body weight)–1) on D3 in the first replication. In Brown Norway rats, ADX induced a high but transient increase of the [Na+]/[K+] ratio on D2 after ADX instead of a continuous increase from D2 to D5 as expected. Therefore, aldosterone was administered on D2 in this strain in the second set of measurements. Fischer 344 rats were injected on D3 as they responded to ADX almost as expected from our preliminary experiment in Wistar rats.

ADX and chronic replacement treatments.  During this period, ADX rats were randomly allocated to two experimental groups: (1) the ADX + aldo group (n = 11) received tap water with increasing concentrations of aldosterone (0.20, 1.00, 5.00 and 25.0 µg (ml drinking fluid)–1) for 4 days each, with a 3-day washout period separating two successive treatments; (2) the ADX + RU group (n = 10) was similarly treated with RU28362 at respective concentrations of 0.04, 0.20, 1.00 and 5.00 µg (ml tap water)–1. The concentration of ligand to give to each strain was calculated every day in order to take into account the difference of fluid intake between Brown Norway and Fischer 344 rats (rats received equal amount of ligand per unit of body weight). The concentrations of aldosterone and RU28362 were chosen from our previous results (Marissal-Arvy et al. 2000) and published data (Uete & Venning, 1962; Campen et al. 1983; Kenyon et al. 1984). The sham group (n = 10) was given tap water. Because stock solutions of steroids were made in ethanol, all drinking fluids contained 1% ethanol.

Salt preference (experiment 2)

At the end of experiment 1, ADX and sham rats of both strains, kept in individual metabolism cages, were submitted to free choice sessions between tap water and saline at increasing salt concentrations (4.5, 9, 18 and 27 g (l water)–1) for 6 days each. Fluid intake was determined by weighing the bottles every 2 days.

Measurements of urinary Na+ and K+ concentration and osmolarity.  Daily urine samples were diluted 5-fold with distilled water to fit the detection limits of the measuring devices. Determinations of Na+ and K+ concentrations were made using an Electrolyte 2 (Beckman) and osmolarity with an Osmomat (Gonotec). Urinary electrolyte values are expressed as mmol osmol–1 to correct for urinary volume variations.

ADX check.  Animals were killed by decapitation. Trunk blood was collected into chilled tubes coated with a 10% EDTA solution and centrifuged (4500 g, 15 min, 4°C) in order to extract plasma, which was stored at –80°C for subsequent measurements of corticosterone. Plasma corticosterone concentrations were determined by competitive protein binding following extraction with absolute ethanol; [3H]corticosterone was used as the radioligand and Rhesus monkey serum as the source of transcortin (Sarrieau & Mormede, 1998). ADX rats showed plasma corticosterone concentrations below assay detection limits.

Data analysis

The results were regrouped and expressed as means ± S.E.M. Data were analysed by a two-way analysis of variance (ANOVA) with strain (Brown Norway versus Fischer 344) and treatment (ADX and aldo versus sham, or ADX + aldo and ADX + RU versus sham) as two between-subjects and one within-subject (time). Post hoc Newman-Keuls tests were performed when the ANOVA was significant (P < 0.05).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Experiment 1: control measurements, ADX and acute administrations of aldosterone

This period corresponded to nine measurements in intact rats and 11 measurements in ADX rats compared to sham-operated rats in both strains.

Body weight.  Body weight is shown in Table 1. ANOVA showed significant main effects for strain (P < 0.001) and treatment (P < 0.001), and a strain–treatment interaction (P < 0.01). As classically described, the control Brown Norway rats were lighter than the Fischer 344 rats (P < 0.001). In Brown Norway rats, ADX had no effect on body weight. By contrast, in Fischer 344 rats, ADX induced a large weight drop from D3 onwards, and decreased body weight gain as compared to controls (P < 0.001).


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  		Table 1.  Body weight and fluid intake in basal conditions, and 5 and 10 days after ADX
 
Food intake.  Food intake data are not shown. ANOVA showed strain (P < 0.001) and ADX effects (P < 0.05). In both strains, the food intake of intact rats was on average 19.4 ± 0.2 g day–1. In Brown Norway rats, the food intake of ADX rats closely followed the food intake of sham-operated rats. On the other hand, the food intake of Fischer 344 rats decreased markedly during the first week after ADX (–61.1%, P < 0.001, on D3). Eight days after surgery, the food intake of ADX rats reached the level of the sham group in Fischer 344 rats.

Fluid intake.  Table 1 shows fluid intake. Strain (P < 0.001) and treatment (P < 0.001) effects were revealed by ANOVA. In both strains, ADX increased water intake, but to a greater extent in Fischer 344 than in Brown Norway rats (+5.10 ± 1.40 ml (100 g body weight)–1, P < 0.001, versus +2.11 ± 0.56 ml (100 g body weight)–1, P < 0.05, respectively, on D10).

Urinary measurements: urinary volume.  The data for urinary volume are not shown. ANOVA showed strain (P < 0.001) and ADX effects (P < 0.001). Data showed high inter-individual and inter-day variability. ADX increased urinary volume, to the same extent as it increased fluid intake in both strains (6.6 ± 0.3 ml day–1 in ADX versus 4.2 ± 0.5 ml day–1 in sham group in the Brown Norway strain, P < 0.05, on D10; 6.4 ± 0.3 ml day–1 in ADX versus 2.9 ± 0.5 ml day–1 in sham group in the Fischer 344 strain, P < 0.05, on D10).

Urinary measurements: Na+ and K+ concentration ratio.  The urinary concentrations of Na+ and K+ are shown in Table 2. Figure 2 shows the basal levels of urinary Na+ and K+. No strain difference was revealed by ANOVA. In Brown Norway and Fischer 344 control rats, the [Na+]/[K+] ratio was between 0.75 and 1.00 during the entire experimental period.


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  		Table 2.  Urinary concentrations of Na+ and K+
 


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  		Figure 2.  Effect of an acute dose of aldosterone on urinary [Na+]/[K+] ratio in basal conditions
After 5 days in metabolism cages, intact Fischer 344 and Brown Norway rats were injected with an acute high dose of aldosterone (100 µg (100 g body weight)–1). Controls received corresponding amounts of vehicle. A water load (3 ml) was administered intraperitoneally to all rats. Urine was collected for 8 h after injection, and diluted 5-fold with distilled water. [Na+]/[K+] ratio determinations were made using an Electrolyte 2 (Beckman). Different from the control group, ***P < 0.001.

 
The acute effect of aldosterone in intact rats is shown in Fig. 2. Subcutaneous injection of an acute high dose of aldosterone did not alter the [Na+]/[K+] ratio in intact Brown Norway rats, whereas this treatment markedly decreased the [Na+]/[K+] ratio in Fischer 344 rats (P < 0.001), reflecting an increase of the urinary K+ concentration ([K+]u) (P < 0.001).

A preliminary study in Wistar rats showed a large increase of the [Na+]/[K+] ratio induced by ADX from the D2 to D6 following ADX (1.17 ± 0.06 on D3 versus 0.79 ± 0.02 in sham-operated animals), mainly caused by a decrease of kaliuresis (– 33.8% versus sham values). [K+]u remained low even after D6 after surgery, whereas the urinary Na+ concentration ([Na+]u) decreased from this day onwards only, bringing the [Na+]/[K+] ratio back to sham levels. In fact, the changes in the excretion of electrolytes after ADX were long lasting in Wistar rats, even though their [Na+]/[K+] ratio returned to normal after a few days. Considering such results, we chose to inject the acute high dose of aldosterone to Brown Norway and Fischer 344 rats on D3 in order to prevent the peak of urinary [Na+]/[K+] ratio induced by ADX, and to compare MR mechanisms between Brown Norway and Fischer 344 rats after ADX.

The effect of ADX in Brown Norway and Fischer 344 rats is shown in Fig. 3. Strain (P < 0.05) and ADX (P < 0.05) effects were shown by ANOVA. In Brown Norway rats, ADX induced a strong but transient increase of [Na+]/[K+] ratio on D2 (P < 0.001), due to variations in both [Na+] and [K+] (P < 0.001 and P < 0.01, respectively). These changes were observed on D2 only, [Na+]u and [K+]u returning to sham values from this day on.



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  		Figure 3.  Acute effect of aldosterone on urinary [Na+]/[K+] ratio after ADX
Half of the ADX rats (n = 11 per strain) were injected with an acute high dose of aldosterone on the third day after ADX (D3) in Fischer 344 rats and on the second and the third days after ADX (D2 and D3) in Brown Norway rats, in order to prevent the peak of urinary [Na+]/[K+] ratio that was induced at different times by ADX in these rat strains. Different from the sham-operated group, *P < 0.05, **P < 0.01, ***P < 0.001.

 
In Fischer 344 rats, ADX induced a marked and long-lasting increase of the [Na+]/[K+] ratio (P < 0.01), maximal on D3, by both an increase of [Na+]u (P < 0.05) and a decrease of [K+]u (P < 0.001). The [Na+]/[K+] ratio remained higher in ADX than in sham groups during the whole experiment in this strain.

The acute effect of aldosterone in ADX rats is shown in Fig. 3. On D3 the injection of an acute high dose of aldosterone restored the [Na+]/[K+] ratio to the basal value in Fischer 344 ADX rats, by returning mainly the [Na+]u to sham levels, but had no effect in Brown Norway rats (data not shown). As the [Na+]/[K+] ratio peak occurred on D2 in Brown Norway rats, we injected aldosterone on this day in Brown Norway ADX rats in the second experimental series.

On D2 the acute injection of aldosterone only partly reduced the increase of the [Na+]/[K+] ratio provoked by ADX in Brown Norway rats (–64.5%, P < 0.001), mainly by an effect on natriuresis (P < 0.01 compared to the ADX group).

Experiment 1: ADX and chronic replacement treatments

As shown in Fig. 1, three groups were compared: sham-operated rats receiving a 1% ethanol solution in tap water; ADX rats receiving aldosterone in their drinking fluid; and ADX rats receiving RU28362, in increasing doses. This period corresponded to four series of 4-day measurements per dose of aldosterone or RU28362 in ADX rats, compared to intact rats, with a 3-day washout period separating each treatment from the next.

Body weight.  The results of body weight are shown in Table 3. Strain (P < 0.05) and treatment (P < 0.05) effects were revealed by ANOVA. Chronic treatment with aldosterone had no effect in Brown Norway ADX rats. In Fischer 344 rats, aldosterone compensated for ADX at the 1.00 µg ml–1 dose and higher.


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  		Table 3.  Body weight during chronic replacement treatments after ADX
 
RU28362 caused a dose-dependent weight loss in both strains, but to a greater extent in Brown Norway rats (–20.3% in Brown Norway versus –12.8% in Fischer 344 rats at the highest dose, compared to the sham values). The third dose of RU28362 (1.00 µg (ml drinking fluid)–1) was sufficient to cause a significant decrease of body weight in Brown Norway rats (P < 0.05), whereas the highest dose only was effective in Fischer 344 rats (P < 0.01).

Food intake.  The data for food intake are not shown. ANOVA did not reveal any significant effect of treatments on food intake.

Fluid intake.  The data for food intake are shown in Fig. 4. ANOVA showed significant main effects for strain (P < 0.05) and treatment (P < 0.001), and a strain–treatment interaction (P < 0.05).



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  		Figure 4.  Fluid intake during chronic replacement treatments after ADX
Ten days after surgery, ADX rats were randomly allocated to two experimental groups: (1) the ADX + aldo group (n = 11) received tap water with aldosterone at four increasing doses (0.20, 1.00, 5.00 and 25.0 µg (ml drinking fluid)–1) for 4 days each, with a 3-day washout period separating each treatment from the next; (2) the ADX + RU group (n = 10) was similarly treated with RU28362 at respective concentrations of 0.04, 0.20, 1.00 and 5.00 µg (ml tap water)–1. Values correspond to the 4th day of the treatments. Different from the sham-operated group, *P < 0.05, ***P < 0.001.

 
In both strains, water intake was larger in ADX versus sham-operated rats, and aldosterone induced a dose-dependent decrease of fluid intake (P < 0.001). In Fischer 344 rats, the lowest dose of aldosterone restored the fluid intake of ADX rats to sham values, whereas in Brown Norway rats, this effect began with the 1.00 µg ml–1 dose only.

RU28362 given at the lowest dose restored the water intake of the ADX group to sham values in both strains. In the Fischer 344 strain, The ADX + RU group showed a lower fluid intake than the ADX + aldo and sham groups (P < 0.05) during the 4th period of treatment.

Urinary measurements: urinary volume.  The data for urinary volume are not shown. ANOVA showed strain (P < 0.001) and treatment (P < 0.01) effects, and a strain–treatment interaction (P < 0.05). Data showed a high inter-individual and inter-day variability. In both strains, urinary production followed fluid intake changes, that is a dose-dependent decrease induced by aldosterone, which was significant at the lowest dose in Fischer 344 rats and at the 1.00 µg ml–1 dose in Brown Norway rats. RU28362 equalized urinary volumes of the sham-operated and ADX groups in both strains.

Urinary measurements: Na+ and K+ concentration ratio.  Figure 5 shows [Na+]/[K+] ratio data. ANOVA showed strain (P < 0.001) and treatment (P < 0.001) effects, and a strain–treatment interaction (P < 0.01). Data are expressed as percentages of the sham group means.



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  		Figure 5.  Urinary [Na+]/[K+] ratio in response to increasing doses of aldosterone (top panel) or RU28362 (bottom panel) after ADX
The ADX + aldo group (n = 11) received tap water with increasing concentrations of aldosterone (0.20, 1.00, 5.00 and 25.0 µg (ml drinking fluid)–1) for 4 days each, with a 3-day washout period separating two successive treatments. The ADX + RU group (n = 10) was similarly treated with RU28362 at respective concentrations of 0.04, 0.20, 1.00 and 5.00 µg (ml tap water)–1. The data are expressed as percentages of the sham group means. Different from the sham-operated group, *P < 0.05, **P < 0.01, ***P < 0.001. Different from the ADX + aldo group, #P < 0.05, ##P < 0.01, ###P < 0.001. The strain differences are described in the text.

 
Aldosterone treatment at increasing doses.  The lowest dose of aldosterone had no effect in Brown Norway rats, whereas this treatment restored the [Na+]/[K+] ratio of ADX rats to sham values (mainly by increasing kaliuresis, Table 2) in Fischer 344 rats. In both strains, at the 1.00 µg ml–1 and higher doses, aldosterone decreased the [Na+]/[K+] ratio on the first two days of each successive treatment, without any clear dose–effect relationship. The decrease of [Na+]/[K+] ratio by aldosterone was caused by a decrease of natriuresis in Fischer 344 strain only, and an increase of kaliuresis in both strains. The decrease of the [Na+]/[K+] ratio induced by aldosterone was globally larger in Fischer 344 than in Brown Norway rats (–30.3% versus –20.5%, P < 0.05). In both strains, an escape from the effect of aldosterone occurred during the last two days of each treatment with a rebound during the washout period. The [Na+]/[K+] ratio returned to or exceeded ADX values, by effects on both Na+ and K+ excretion (data not shown).

RU28362 treatment at increasing doses.  In Fischer 344 rats, the first dose of RU28362 restored the [Na+]/[K+] ratio of the ADX group to the sham values by a kaliuretic effect, compared to ADX values, whereas this dose induced an increase of [Na+]/[K+] ratio by a natriuretic effect in Brown Norway rats (P < 0.05). Such an increase became significant from the 1.00 µg ml–1 dose only in Fischer 344 rats (P < 0.01).

Experiment 2: salt preference

The results of experiment 2 are shown in Fig. 6. ADX and sham-operated rats of both strains were given free choice between tap water and saline at increasing salt concentrations (4.5, 9, 18 and 27 g (l water)–1).



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  		Figure 6.  Saline preference
ADX and sham-operated rats of both strains were submitted to a free choice between tap water and saline at increasing salt concentrations (4.5, 9, 18 and 27 g (l water)–1) for 6 days each. Fluid intakes are expressed as percentages of the total amount of fluid ingested. Different from the sham group, *P < 0.05.

 
ANOVA showed strain (P < 0.001) and treatment (P < 0.05) effects. Contrary to Brown Norway rats (P < 0.001), Fischer 344 sham rats showed a very low appetite for saline. In the Brown Norway strain, sham-operated rats showed a high intake of saline which decreased in a salt concentration-dependent manner.

In both strains, as shown in experiment 1, fluid intake was higher in ADX than in sham groups (P < 0.05 in Brown Norway, P < 0.001 in Fischer 344 rats). In Fischer 344 rats, ADX increased salt appetite at the three lowest concentrations (P < 0.05). In Brown Norway rats, the ADX group showed a slightly higher salt appetite than the sham-operated group for the 9 g l–1 concentration only (P < 0.05), whereas ADX and sham curves were identical for the three other concentrations.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The aim of this study was to compare corticosteroid effects on excretion of electrolytes in two rat strains, Brown Norway and Fischer 344, characterized by strong functional differences in their corticosteroid receptors. Results from our previous studies (Marissal-Arvy et al. 1999, 2000) clearly suggested that the MR-related pathways could be active even in absence of corticosteroids in Brown Norway rats, and that GR responses to corticosterone or RU28362, a specific GR agonist, were greater in Brown Norway than in Fischer 344 rats. As hydroelectrolytic balance is modulated by both corticosteroid receptors (Muller et al. 2003), we made a comparative investigation of the effect of ADX and of MR/GR-mediated actions on sodium and potassium excretion in these two rat strains. The use of aldosterone and RU28362 given in increasing doses to ADX Brown Norway and Fischer 344 rats allowed us to distinguish mineralocorticoid from glucocorticoid actions on electrolyte excretion.

The effects of corticosterone on body weight follow a bell-shaped curve with increasing concentrations of the hormone (Devenport et al. 1989) as a result of different components of corticosterone actions on consumatory behaviours and metabolism (Tempel & Leibowitz, 1994; Santana et al. 1995). Optimal growth is reached at physiological levels. Body weight gain is reduced by ADX, restored to normal by low doses of corticosterone or by MR agonists (Devenport et al. 1991), and decreased by high doses of corticosterone or by GR agonists via catabolic effects on fat and protein stores (Santana et al. 1995). In contrast to Fischer 344 rats, which followed the expected curve, the body weight gain of Brown Norway rats was completely insensitive to ADX, as previously described (Marissal-Arvy et al. 2000), and the same dose of RU28362 induced a greater weight loss in Brown Norway than in Fischer 344 rats, confirming the hypothesis of greater efficacy of GR-mediated mechanisms in these rats. The low doses of RU28362 used in the present study did not induce lower food intake but rather catabolic effects via GRs to induce weight loss (Santana et al. 1995).

ADX is well known to increase fluid intake and urinary volume (Horisberger & Rossier, 1992), mainly by inducing a high renal sodium loss (Verrey, 1995), pulling water through epithelia. Diuresis and water intake were increased by ADX to a greater extent in Fischer 344 than in Brown Norway rats, in the same proportion as in our previous experiments (Marissal-Arvy et al. 1999, 2000).

Absence of corticosteroids does not obviously alter MR-mediated functions in Brown Norway rats (no weight loss, limited increase of fluid intake), suggesting the implication of unusual properties in their MR pathway, or the involvement of compensatory mechanisms to ADX in these rats. Indeed, several mechanisms have been involved in MR function. For instance, urinary production and electrolyte composition depend on many factors such as vasopressin (Alfaidy et al. 1995), angiotensin II (Fregly & Rowland, 1985), kallikrein and atrial natriuretic factor (De Bold et al. 1981; Franci, 1994) or catecholamines (Zabik et al. 1993), alone or in interaction with corticosteroid receptor-related pathways. In this study, we aimed to compare the response of electrolyte excretion to the MR agonist aldosterone in basal condition and after ADX between Brown Norway and Fischer 344 rat strains.

The alteration of the [Na+]/[K+] ratio is the most accurate reflection of mineralocorticoid action (Kagawa et al. 1957) and measuring this ratio has the advantage of setting us free from urinary evaporation in metabolism cages (the two doses being equally affected), and of amplifying variations (the two parameters varying in opposite ways in response to a lack or an excess of mineralocorticoids). The [Na+]/[K+] ratio can be altered by aldosterone or deoxycorticosterone via MRs (Funder, 1993; Argawal, 1994), but also by corticosterone or synthetic glucocorticoids such as dexamethasone or RU28362 via GRs (Teutsch et al. 1981; Campen et al. 1983; Muller et al. 2003). Na+ and K+ excretions are intimately correlated, as an increase of natriuresis induces a decrease of kaliuresis, mainly via the antiport provided by the Na+–K+-ATPase (Shimizu et al. 1989; Nonaka et al. 1992).

As classically described (Muller et al. 2003), by its anti-natriuretic and kaliuretic effects, aldosterone decreased the [Na+]/[K+] ratio in Fischer 344 intact rats. This treatment did not alter the [Na+]/[K+] ratio (no effect on natriuresis or kaliuresis) in intact Brown Norway rats, suggesting a reduced sensitivity of MRs to its agonist in these rats.

Conversely, ADX is classically shown to increase the [Na+]/[K+] ratio (Booth et al. 2002), with a return to basal value 5–7 days after surgery, as was confirmed by our preliminary study in Wistar rats. In the Fischer 344 strain, ADX induced the expected increase of the [Na+]/[K+] ratio. This effect lasted during the whole design, combining an increase of natriuresis and a decrease of kaliuresis. In Brown Norway rats, an increase of the [Na+]/[K+] ratio was also observed after ADX, higher but more transient than in Fischer 344 rats, with a peak the day after surgery (D2) only.

In order to investigate what part of these increases of [Na+]/[K+] ratio involved MR-mediated actions, we injected ADX rats with an acute high dose of aldosterone, on D3 in the Fischer 344 strain and on D2 in the Brown Norway strain, when the effects of ADX were highest, respectively. This treatment completely reversed the increase of the [Na+]/[K+] ratio induced by ADX in Fischer 344 rats, but only part of the [Na+]/[K+] ratio peak observed in Brown Norway rats. This failure could be due to the dose of aldosterone, insufficient to activate the Brown Norway MRs, showed to be less sensitive to its ligands than the MRs of Fischer 344 rats. This would be very surprising because the aldosterone dose used was supraphysiological. These results favour the hypothesis of a mixed origin of the [Na+]/[K+] ratio peak induced by ADX in Brown Norway rats, that could involve many other factors, in addition to MR effects, involved in the electrolytic balance and modulated by corticosteroids (Alfaidy et al. 1995; Marunaka, 1997). The fast return of the [Na+]/[K+] ratio to the basal value occurred by the restoration of natriuresis and kaliuresis to sham values in Brown Norway rats, but not in Wistar or Fischer 344 rats whose excretion of electrolytes was definitively disturbed by ADX.

Then, we aimed to compare the effects of chronic replacement treatments after ADX between Brown Norway and Fischer 344 rats. ADX rats received increasing doses of aldosterone or RU28362 via their drinking fluid in four periods of 4 days, each separated by a 3-day washout period. The chronic treatment with aldosterone at the lowest dose had no effect in ADX Brown Norway rats, whereas it restored the [Na+]/[K+] ratio of ADX Fischer 344 rats to sham values. The next three doses decreased the [Na+]/[K+] ratio on the first 2 days of treatment in both strains, but to a greater extent in Fischer 344 than in Brown Norway rats, in accordance with a lower sensitivity of the Brown Norway MR pathway to aldosterone. Each decrease of the [Na+]/[K+] ratio induced by aldosterone was followed by an escape from the treatment during the next 2 days and a rebound during the washout period, as observed before (but not discussed) by Kenyon et al. (1984). This effect probably involves regulatory factors such as vasopressin, Na+ and K+ channels or Na+–K+-ATPase (Horisberger & Rossier, 1992; Grillo et al. 1997), activated in this case more by MR-dependent mechanisms than by alterations of the [Na+]/[K+] ratio as it already occurred with the lowest dose of aldosterone in both strains.

After ADX, the Brown Norway rat MRs became reactive to its agonist whereas MR-mediated effects were apparently not activated by an acute high dose of aldosterone in control conditions. The Brown Norway rat MRs may be saturated by endogenous aldosterone in basal conditions. Nevertheless, no greater density or affinity (Marissal-Arvy et al. 1999), neither higher plasma levels of aldosterone (unpublished data), nor higher blood pressure (Pravenec et al. 2003), have been shown in Brown Norway compared to Fischer 344 rats. Compensatory mechanisms involved in the insensitivity of Brown Norway rats to ADX could also be implicated in the reduced sensitivity of the MR pathway to its agonist in intact Brown Norway rats.

Even though 11ß-hydroxysteroid dehydrogenase 2 prevents the access of corticosterone to MRs and GRs in kidney (Alfaidy et al. 1995), an acute stress can increase natriuresis via GRs (Campen et al. 1983; Kenyon et al. 1984), that was described all along the loop of Henle and in the renal tubules (Todd-Turla et al. 1993; Bonvalet, 1998). Synthetic agonists such as RU28362 can activate renal GRs and alter the urinary Na+/K+ ratio. GR-mediated effects on this ratio are less clear than MR actions, as both natriuretic and kaliuretic effects can be induced via GRs (Campen et al. 1983; Kenyon et al. 1984; Muller et al. 2003). During chronic treatments in ADX animals, the lowest dose of RU28362 (0.04 µg (ml drinking fluid)–1) induced an increase of the [Na+]/[K+] ratio in the Brown Norway strain, whereas this effect occurred only with the 1.00 µg (ml drinking fluid)–1 dose in Fischer 344 rats, which supports the hypothesis of a greater sensitivity of GR mechanisms to RU28362 in Brown Norway rats. In both rat strains, RU28362 acts on natriuresis in two steps: a transient natriuretic effect, followed by the restoration of the natriuresis of the ADX group to sham value. These opposed effects were both previously described, but independently, and therefore GR-mediated effects on natriuresis remain much debated. The classically described kaliuretic GR-mediated effect (Campen et al. 1983; Muller et al. 2003) was not seen in this study, probably because it was hidden by the inhibitory effect exerted by Na+ on kaliuresis (antiport to the ATPase level and K+ channel modulation by this cation, Shimizu et al. 1989; Nonaka et al. 1992). A GR-mediated kaliuresis might appear at higher doses of RU28362.

As sodium homeostasis includes salt appetite regulation (Pietranera et al. 2001), we also compared saline preference between Brown Norway and Fischer 344 rats. Salt appetite is regulated by many factors such as adrenocorticotropic hormone, atrial natriuretic factor and mineralocorticoids acting synergistically with the central renin–angiotensin system (De Kloet et al. 1993; Riftina et al. 1995). The central sites of action of aldosterone on salt appetite are medial amygdala, circumventricular organs and anterior hypothalamus. Both ADX and high doses of aldosterone or deoxycorticosterone increase salt appetite in rats (Ly et al. 1997; Grillo et al. 1997). Brown Norway and Fischer 344 rats were submitted to a free choice between tap water and saline at increasing salt concentrations. Saline preference was very different between the two strains of rats. As previously described (Devenport & Stith, 1992), sham Fischer 344 rats were weakly attracted by saline. On the contrary, sham-operated Brown Norway rats showed a strong appetite for salt, which decreased in a concentration-dependent manner. In the Brown Norway strain, the ADX group showed a slightly higher salt appetite than the sham group for the 9 g l–1 concentration only, whereas this difference was stronger and occurred at the lowest three salt concentrations in Fischer 344 rats. The increase of salt appetite induced by ADX was larger in Fischer 344 than in Brown Norway rats, in agreement with a lower sensitivity of Brown Norway rats to ADX.

Taken as a whole, for excretion of electrolytes, the Fischer 344 rat strain can be considered as a control strain where classical responses to ADX and aldosterone are produced. Our data support our previous hypotheses about the differences in MR/GR mechanisms in Brown Norway and Fischer 344 rat strains: (1) a very limited effect of ADX in Brown Norway rats on body weight, food and fluid intake, diuresis, natriuresis and kaliuresis and salt appetite, in accordance with the occurrence of active MR-related pathways even in the absence of adrenal steroids; (2) a lower sensitivity to aldosterone in ADX Brown Norway rats than in ADX Fischer 344 rats, and an insensitivity to aldosterone in intact Brown Norway rats; (3) a greater sensitivity of GR-related mechanisms to RU28362 in Brown Norway than in Fischer 344 rats on body weight gain and electrolyte excretion. Considering that both MRs and GRs regulate hypothalamic–pituitary–adrenal axis processes, such functional differences in corticosteroid receptors could be at the origin, at least partly, of the strain differences in corticotropic activity/reactivity to stress (Sarrieau & Mormede, 1998). Sequencing of the MR gene and quantitative trait locus mapping are currently in progress in order to identify the molecular bases of such differences in corticosteroid receptor function between Brown Norway and Fischer 344 rats.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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   Acknowledgements
 
The authors thank Roussel Uclaf (Romainville, France) for the generous gift of RU28362. We also thank Drs Lyse Bankir and Alain Doucet for helpful suggestions.




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