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Experimental Physiology 90.6 pp 847-853
DOI: 10.1113/expphysiol.2005.030619
© The Physiological Society 2005
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CNS-induced natriuresis, neurohypophyseal peptides and renal dopamine and noradrenaline excretion in prehypertensive salt-sensitive Dahl rats

Mats Sjöquist1, Siu-Lan Lee1 and Peter Hansell1

1 Section of Integrative Physiology, Department of Medical Cell Biology, Biomedical Centre, University of Uppsala, Sweden


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
To identify defects in the salt-sensitive Dahl rat (Dahl-S), the natriuretic, catecholaminergic and pressor responses to 60-min elevation of the cerebroventricular sodium concentration (CNS-induced natriuresis) were compared between prehypertensive salt-sensitive Dahl-S and salt-resistant Dahl rats (Dahl-R). The plasma concentrations of the rat natriuretic hormone oxytocin, which has implications for the development of hypertension, and vasopressin (AVP) were also measured. Basal sodium and catecholamine excretion and mean arterial blood pressure (MAP) were similar in both strains. Sodium excretion during CNS stimulation increased more than 15-fold in Dahl-R but only 10-fold in Dahl-S. Dopamine excretion increased only transiently and similarly in both strains. Noradrenaline excretion and response to CNS stimulation were similar, suggesting a comparable sympathetic nervous activity between the strains. MAP increased comparably in Dahl-R and Dahl-S. Plasma AVP concentration was similar in both strains while plasma oxytocin concentration after CNS stimulation was more than 2-fold higher in Dahl-S than in Dahl-R. In conclusion, the prehypertensive Dahl-S has an attenuated natriuretic response to elevations of the cerebroventricular fluid sodium concentration and a higher plasma level of the natriuretic hormone oxytocin. Dopamine is not a mediator of CNS-induced natriuresis in neither strain. The attenuated natriuretic response may partly explain the salt-sensitivity in Dahl-S, and the higher plasma oxytocin value may either represent an effort to compensate for the deficient natriuretic response or reflect a primary defect in this system. Due to the known involvement of oxytocin in central MAP regulation in some hypertensive animal models, the findings warrant further investigation.

(Received 13 April 2005; accepted after revision 8 August 2005; first published online 9 August 2005)
Corresponding author P. Hansell: Section of Integrative Physiology, Department of Medical Cell Biology, University of Uppsala, Biomedical Center, PO Box 571, S-751 23 Uppsala, Sweden. Email: peter.hansell{at}medcellbiol.uu.se


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The aetiology of primary hypertension is still unknown; however, there is evidence that the initial hypertensive trigger resides within the kidney (Dahl & Heine, 1975; De Wardener, 1990a,b, 2001). An inability to accurately respond with natriuresis during a sodium load results in sodium retention, which has been suggested to be intricately connected to the development of hypertension (Osborn, 1991). The salt-sensitive Dahl rat (Dahl-S), as opposed to the salt-resistant Dahl rat strain (Dahl-R), develops hypertension when fed a high-sodium diet, and an elevation of the cerebrospinal fluid sodium concentration precedes the increase in mean arterial blood pressure (MAP) (Huang et al. 2004). The salt sensitivity in Dahl-S, may be due to a defect in one or more of several systems involved in fluid and electrolyte balance, including nitric oxide (NO) (for review see Manning et al. 2001) and dopamine (DA) receptors (for review see Aperia, 2000), or it may be due to increased oxidative stress (for review see Manning et al. 2003).

In previous studies in prehypertensive Dahl-S, we found that the natriuretic response to acute isotonic volume expansion is similar to that in Dahl-R in spite of a detected defective dopamine DA1-receptor (Hansell, 1995; Möller & Hansell, 1995). This would suggest that other mechanisms involved in sodium homeostasis have compensated for the defective DA1 response. The present study was undertaken to elucidate whether any differences exist between Dahl-R and Dahl-S in the natriuretic, catecholaminergic and pressor response to elevations of the cerebroventricular sodium concentration (CNS-induced natriuresis) which could explain the salt-sensitivity of Dahl-S. This type of natriuresis (hypernatraemic-induced) is mediated over other hormones/mechanisms than those after isotonic volume expansion (hypervolaemia-induced) (Andersson et al. 1966; Hansell et al. 1987; Hansell & Fasching, 1991; Huang et al. 1995, 1996). Previous studies from this and other laboratories have demonstrated that in the rat oxytocin (OT) is a natriuretic hormone (for review see Gimple & Fahrenholz, 2001) and an important mediator of CNS-induced natriuresis (Huang et al. 1995, 1996). OT is released together with arginine vasopressin (AVP) from neurones in the paraventricular and supraoptic nuclei during a hyperosmotic stimulus (Brimble & Dyball, 1977; Brimble et al. 1978). Increased OT activity may be involved in the development of some forms of hypertension possibly by increasing the activity/sensitivity of central AVP V1-receptors (for review see Yang et al. 2004).

The aim of the present study was to investigate defects in the prehypertensive Dahl-S which may have consequences for its susceptibility to develop hypertension during increased sodium intake. We therefore challenged animals with a central sodium load and measured the natriuretic response with OT, catecholamines and AVP, which are all known to effect natriuresis. OT was included because of its involvement in central blood pressure regulation and possible involvement in animal models of hypertension. Furthermore, no previous studies have examined whether differences exist between the two Dahl strains in plasma OT levels after a hypernatraemic challenge.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experiments were approved by the local ethics committee in Uppsala. The study was performed on nine male Dahl-R and nine male Dahl-S (Möllegaard Breeding Centre, Copenhagen, Denmark) weighing 267 ± 5 g and 268 ± 4 g, respectively. During the 7 days prior to the experiments, all animals had free access to tap water and standardized chow (R3, Ewos, Södertälje, Sweden) containing 0.3% sodium, 0.8% potassium and 21% protein. The animals were anaesthetized with an intraperitoneal injection of Inactin (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium; 120 mg (kg body weight)–1; Byk-Gulden, Konstanz, Germany) and placed on a servo-controlled heating pad to maintain the body temperature at 37.5°C. The experiments were performed under full anaesthesia.

Surgical procedure

All animals were tracheostomized and a polyethylene catheter was inserted into the right femoral artery for continuous measurement of MAP and for blood sampling. The bladder was catheterized through a suprapubic incision for urine sampling. A metal cannula was inserted into the right lateral cerebral ventricle using a stereotaxic technique. A skin incision was made over the right parietal bone and a 1-mm hole was drilled through the bone, 0.8 mm posterior to the bregma and 1.5 mm lateral to the mid-sagittal suture. A stainless steel cannula (outer diameter, 0.30 mm) was inserted and cemented to the skull with Schnellklebsstoff X-60 (HBM GmbH, Germany). Through this cannula an artificial cerebrospinal fluid (CSF) containing (mM): NaCl 126, NaHCO3 25, MgCl2 0.8, CaCl2 1.14, NaH2PO4 0.5 and KCl 3 was infused. Stimulation of the central mechanisms was achieved by changing to a solution containing 1 M NaCl (NaCSF). Both solutions were infused at a rate of 520 nl min–1. The concentration of NaCl in the NaCSF with the chosen infusion rate is a well-documented potent stimulus of natriuresis (Sjöquist et al. 1986; Hansell et al. 1987, 2000).

Protocol

After completion of the surgical procedures, the animals received CSF intracerebroventricularly and were allowed to recover for 45 min. Two consecutive periods of urine collection lasting 20 min each were then commenced, and served as controls (C1 and C2). MAP was monitored continuously throughout the experiments. After these 40 min of control sampling, the animals were stimulated intracerebroventricularly with NaCSF for 60 min, during which time urine was collected continuously in three consecutive 20-min periods (E3–E5). At the end of the 60 min of CNS stimulation, 2 ml blood was collected into a polypropylene container pretreated with 3 mg EDTA. The kidneys were then excised, and weighed after removal of blood. At the end of the experiment, while the animals remained fully anaesthetized they were killed with an intravenous injection of saturated KCl.

Urine analysis

The urine volumes were measured gravimetrically. Urinary sodium (UNa) and potassium concentrations (UK) were determined by flame photometry (FLM3, Radiometer, Copenhagen, Denmark) and the urine osmolality was measured from the depression of the freezing point (Model 3MO, Advanced Instr Inc., MA, USA). The urine samples to be analysed for their dopamine (DA) and noradrenaline (NA) contents were transferred to polyethylene vials containing 1 ml 0.4 M perchloric acid, 0.1 ml 10% EDTA and 0.05 ml 5% Na2S2O5, and immediately frozen to –70°C until required for analysis. The urinary DA and NA contents were measured electrochemically after alumina adsorption and ion-pair, reversed-phase high-performance liquid chromatography (HPLC). The main metabolite of DA, dihydroxyphenylacetic acid formed by monoaminoxidase (DOPAC), was followed in parallel. An internal standard (3,4dihydroxybenzylamine; DHBA) was used and all values were corrected for its recovery. The accumulated sodium and DA excretion were calculated as the sum of the respective excretion throughout the 60 min of CNS stimulation and was used as an index of the ability of the animals to respond with natriuresis and to generate DA.

Plasma analysis

The blood samples were centrifuged at 1100 g for 10 min at 4°C and the plasma was transferred to new polypropylene vials which were immediately frozen at –70°C pending analysis. The plasma concentrations of AVP and OT were estimated from radioimmunoassays as described previously in detail (Magnusson & Meyerson, 1993; Huang et al. 1994). AVP and OT were from Ferring, Sweden. Typical characteristics for the assay for OT and AVP were: sensitivity, 5 and 0.31 pg ml–1, respectively; intra-assay coefficient of variation (cv), 11 and 8%, respectively; interassay cv, 16 and 20%, respectively (Huang et al. 1994, 1995, 1996).

Statistical analysis

All data are presented as mean ± 1 S.E.M. Differences within and between each group were tested with analysis of variance (ANOVA) followed by Student's t test for independent or dependent sample means where appropriate. During multiple measures, correction according to the Bonferroni method was performed. A P-value of less than 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Basal values for all measured variables were similar in Dahl-R and Dahl-S. CNS stimulation with a hypertonic sodium solution gave rise to a potent natriuretic (Fig. 1) and kaliuretic (Table 1) response and to an elevation of MAP. Renal catecholamine excretion increased only transiently in both strains (Fig. 1 and Table 2). In Dahl-R (kidney weight, 2.07 ± 0.04 g), sodium excretion (Fig. 1) increased more than 15-fold (P < 0.05) after 60 min of CNS stimulation. The increase was composed of increments in both urine flow rate (more than 4-fold) and urinary sodium concentration (more than 3-fold) (Table 1). In Dahl-S (kidney weight, 2.12 ± 0.04 g), sodium excretion only increased 10-fold (P < 0.05) following 60 min of CNS stimulation which was significantly less than that in Dahl-R (P < 0.05). The accumulated sodium excretion during CNS stimulation in Dahl-R was 102 ± 14 µmol (60 min)–1 which was higher than the corresponding value in Dahl-S (74 ± 12 pmol (60 min)–1, P < 0.05). Dopamine excretion increased only transiently in both strains and was not different from control conditions during the maximal natriuretic response (Fig. 1). The accumulated dopamine excretion (Fig. 2) during CNS stimulation was similar in Dahl-R and Dahl-S (127 ± 7 and 119 ± 11 ng (60 min)–1, respectively). DOPAC excretion was still slightly elevated above the control level at the end of the CNS stimulation period in Dahl-R (+56%), while it was not significantly different from control conditions in Dahl-S (+34%) (Table 2). Noradrenaline excretion (Table 2) in Dahl-R showed a transient increase during the first 20 min of CNS stimulation but was not different from control conditions during the maximal natriuretic response. A similar excretion pattern for noradrenaline was found in Dahl-S. MAP increased similarly in Dahl-R (+5%) and Dahl-S (+7%). Osmolality increased by 34% in Dahl-R and 21% in Dahl-S, and the kaliuretic response was also similar (8- and 6-fold, respectively) between the strains. Plasma AVP concentration was similar in the strains after 60 min of CNS stimulation (103 ± 15 and 142 ± 37 pg ml–1 for Dahl-R and Dahl-S, respectively) (Fig. 3). However, plasma OT concentration after 60 min of CNS stimulation was higher in Dahl-S (270 ± 69 pg ml–1) than in Dahl-R (122 ± 15 pg ml–1) (P < 0.05) (Fig. 3). In summary, the response to CNS stimulation differed between the strains in only two parameters: sodium excretion and plasma OT concentration. In Dahl-S, the natriuretic response to CNS stimulation was attenuated and only 73% (P < 0.05) of that in Dahl-R. Furthermore, plasma OT concentration was more than 2-fold higher in Dahl-S than in Dahl-R (P < 0.05).



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  		Figure 1.  Sodium and dopamine excretion
Sodium (UNaV, lines) and dopamine (UDAV, bars) excretion before and during CNS stimulation in Dahl-R and Dahl-S. *P < 0.05 versus corresponding period in Dahl-R.

 

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  		Table 1. Arterial blood pressure and urine data before (C1 and C2) and during (E3–E5) CNS-induced natriuresis in Dahl-R (DR) and Dahl-S (DS)
 

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  		Table 2. Urinary noradrenaline and DOPAC excretion before (C1 and C2) and during (E3–E5) CNS-induced natriuresis in Dahl-R (DR) and Dahl-S (DS)
 


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  		Figure 2.  Accumulated sodium and dopamine excretion
Accumulated sodium (UNaV) and dopamine (UDAV) excretion per g kidney weight during CNS-induced natriuresis in Dahl-R (hatched bars) and Dahl-S (open bars). *P < 0.05 versus Dahl-R.

 


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  		Figure 3.  Plasma concentration of vasopressin and oxytocin
Plasma concentration of vasopressin (AVP) and oxytocin (OT) after 60 min of CNS stimulation with hypernatraemic solution in Dahl-R (hatched bars) and Dahl-S (open bars). *P < 0.05 versus Dahl-R.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The aim of the present study was to investigate defects in the prehypertensive Dahl-S which may have consequences for its susceptibility to develop hypertension during increased sodium intake. The results have shown that prehypertensive Dahl-S has an attenuated natriuretic response to an acute elevation of the cerebrospinal fluid sodium concentration and a higher plasma OT concentration as compared with that of Dahl-R. These findings may have implications for the salt sensitivity of Dahl-S.

Dopamine is not an important mediator of the natriuretic response in either Dahl-R or Dahl-S as only a transient increase in excretion occurred. This would indicate that the reported defective dopamine DA1-receptor is not primarily involved in the attenuated response. The effect of CNS stimulation on noradrenaline excretion and arterial blood pressure were also similar in both strains suggesting a comparable activity/sensitivity of the sympathetic nerves. Abnormalities in catecholamine handling do not seem to be primarily responsible for the attenuated CNS-induced natriuretic response in prehypertensive Dahl-S. The higher plasma OT level in Dahl-S may either represent an effort to compensate for the deficient natriuretic response or reflect a primary defect in this system. It is noteworthy that the natriuretic hormones OT, NO and atrial natriuretic peptide are closely related in fluid-volume homeostasis and seem to interact on the cellular level perhaps through a common pathway (for review see Gimple & Fahrenholz, 2001).

In a previous study, we demonstrated that prehypertensive Dahl-S have a similar capacity as Dahl-R to excrete an isotonic saline load, partly through dopamine-sensitive pathways, and to generate dopamine in spite of a detected defect in the DA1-receptor (Hansell, 1995; Möller & Hansell, 1995). This would suggest that compensation has occurred in this strain in order to respond properly to a hypervolaemic challenge. The present study shows that elevation of the cerebrospinal fluid sodium concentration elicits a natriuretic response which is attenuated in Dahl-S and does not primarily involve the dopamine system. This fits well with our previous studies showing that dopamine receptor blockade does not interfere with CNS-induced natriuresis (Hansell et al. 1988a), but affects the natriuretic response to isotonic volume expansion (Hansell et al. 1988b; Hansell & Fasching, 1991). We have also found that dopamine excretion only transiently increases in spontaneously hypertensive rats and in Wistar-Kyoto rats during CNS stimulation, which shows a non-dopamine-mediated natriuretic response in animal models of both normotension and hypertension (Hansell et al. 2000). When combined, the above results show completely different natriuretic mechanisms to hypervolaemia and hypernatraemia. They also show Dahl-S have an attenuated ability to respond to hypernatraemia using non-dopamine-sensitive pathways. It may be suggested that the inability of Dahl-S to respond accurately to hypernatraemia results in sodium retention which may be intricately connected to the development of hypertension (Osborn, 1991) and may therefore partly explain the sodium sensitivity of Dahl-S. In this context, it is interesting to note that in Dahl-S an elevation of the CSF sodium concentration precedes the increase in mean arterial blood pressure (Huang et al. 2004) and that OT is primarily released via osmoreceptors when CSF sodium concentration is elevated (Sjöquist et al. 1995).

In the present study, only two parameters differed between the strains in response to CNS stimulation, namely sodium excretion and plasma OT concentration, of which the implications of the former have been discussed above. The higher plasma concentration of OT in Dahl-S in response to CNS stimulation may have implications for the salt-sensitive hypertension in Dahl-S and may partially explain the attenuated natriuretic response. OT induces natriuresis when infused systemically (Conrad et al. 1986; Huang et al. 1994) or intraperitoneally (Haanwinckel et al. 1995) and its concentration in plasma increases during injection of hypertonic sodium solutions intraperitoneally (Balment et al. 1980), intracerebroventricularly (Sjöquist et al. 1995) and systemically (Verbalis & Dohanics, 1991; Huang et al. 1995). Specific OT receptors have been demonstrated in the kidney (Stoeckel & Freund-Mercier, 1989; Schmidt et al. 1990), and the natriuretic effect of OT can be blocked by specific receptor antagonists (Huang et al. 1994). In light of the above, OT can be regarded as a natriuretic hormone that is involved in sodium homeostasis in the rat (Gimple & Fahrenholz, 2001). The higher plasma concentration of OT found in Dahl-S after CNS stimulation in the present study may either represent an effort to compensate for the attenuated natriuretic ability or it may represent a primary defect in this system. If, for example, a defective renal OT receptor, or defective receptor coupling, exists in Dahl-S it could explain the inability of Dahl-S to appropriately respond with CNS-induced natriuresis, and this would up-regulate the level of synthesis/release of OT. If Dahl-S has an attenuated renal sensitivity to OT, it may partly explain the salt-sensitive hypertension in Dahl-S and the ability to transplant the salt-sensitivity from Dahl-S to Dahl-R (Dahl & Heine, 1975). It is clear that OT is involved in blood pressure regulation and in the development of hypertension in some animal models. Pretreatment of rats with OT sensitizes the AVP V1-receptor-mediated pressor response to AVP (Poulin et al. 1994), and OT knockout mice are hypotensive (Bernatova et al. 2004). Furthermore, in hypertensive dopamine D5-receptor knockout mice, administration of an OT receptor antagonist for 12–24 h (but not acutely) normalizes blood pressure (Hollon et al. 2002). It is thus possible that elevated OT levels, as shown in the present study, can affect central V1 receptor sensitivity leading to an elevation in pressure during chronic conditions. Further chronic studies are required to determine whether the OT system is defective in Dahl-S and the relevance of such a defect to its salt-sensitive hypertension.

An NO deficiency has been found to be of crucial importance for the hypertensive response in Dahl-S to a prolonged elevation in the sodium intake. In studies by Chen & Sanders (1991) and Hu & Manning (1995) it was shown that salt-sensitive hypertension in the Dahl S/Rapp rats was prevented by parental and oral administration of L-arginine. Whether an inability of Dahl-S to produce sufficient amounts of NO is responsible for the attenuated natriuretic response to acute elevation of the CSF sodium concentration in the present study cannot be determined. It is not necessarily the identical operating systems responsible for the natriuretic response during acute versus more chronic changes in sodium loading in Dahl-S and, furthermore, in the prehypertensive versus hypertensive phase. It is, however, noteworthy that OT-induced natriuresis may occur through activation of the renal NO synthase localized in macula densa cells (Wilcox et al. 1992) suggesting an important interaction between these systems.

The similar excretion of noradrenaline and pressor response during CNS stimulation in prehypertensive Dahl-S and Dahl-R would suggest a comparable activity/sensitivity of the sympathetic nervous system. The similar plasma concentration of AVP and effect on urine flow rate and urine osmolality suggest that the two strains have a comparable activity/sensitivity in this system too. As to the transient increase in dopamine excretion, this may largely represent an artefact depending on a ‘wash-out’ effect. When urine flow rate suddenly increases during CNS stimulation, the highly concentrated tubular dopamine will be washed out and give a falsely high value during the first collection period.

It is generally known that anaesthesia affects cardiovascular and brain function. It could therefore be argued that the anaesthetic per se gave rise to the differences in response reported in the present study (i.e. in renal sodium excretion and plasma oxytocin concentration). There are, however, no studies which have suggested that anaesthesia changes renal or hypophyseal function differently in Dahl-R compared to Dahl-S. Furthermore, in a recent study on conscious Dahl rats (Huang et al. 2004), a defective sodium regulation was demonstrated in Dahl-S during a sodium challenge (elevation in CSF sodium concentration). The absolute levels/changes in the measured parameters of the present study may very well be influenced by the anaesthetic used, but the qualitative changes are believed to be similar to those in conscious animals.

The plasma levels of AVP and OT reported in the present study after CNS stimulation are higher than generally reported in the literature after other physiological stimuli in rodents. It is obvious that the stimulation procedure in the present study is extremely potent and may exceed physiological limits. The aim of the present investigation was, however, to determine if the previously reported inability of Dahl-S to regulate sodium balance can be correlated with a differential regulation of OT turnover. It is evident that the present study confirms the relative inability of Dahl-S to respond appropriately to a sodium load and, furthermore, shows a different OT response compared to Dahl-R which may have implications for its sodium sensitivity.

In conclusion, the prehypertensive Dahl-S has an attenuated natriuretic response to elevations of the cerebroventricular fluid sodium concentration and a higher plasma OT concentration. Dopamine is not a mediator of CNS-induced natriuresis in either strain and is therefore most probably not responsible for the attenuated natriuretic response in Dahl-S in spite of the reported defective renal DA1-receptor. The attenuated natriuretic response may partly explain the salt-sensitivity in Dahl-S, and the higher plasma OT value may either represent an effort to compensate for the deficient natriuretic response or reflect a primary defect in this system which may include the renal NO system.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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   Acknowledgements
 
The skilful assistance of Brita Isakson and Angelica Fasching is gratefully acknowledged. Financial support for this study was provided by the Swedish Medical Research Council (project 10840).




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