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. 2001 Dec 15;537(Pt 3):941–947. doi: 10.1111/j.1469-7793.2001.00941.x

Contribution of pressure natriuresis to control of total body sodium: balance studies in freely moving dogs

Erdmann Seeliger 1, Erdal Safak 1, Pontus B Persson 1, H Wolfgang Reinhardt 1
PMCID: PMC2279006  PMID: 11744766

Abstract

  1. This study aims at determining whether elevation of renal perfusion pressure (RPP) may correct for increased total body sodium (TBS), via pressure natriuresis.

  2. Freely moving dogs were studied on four consecutive days. During day 1, low-dose angiotensin II and aldosterone were infused. Pressure natriuresis was prevented by servo-controlling RPP to 20% below the control level. Sodium and water retention increased TBS and total body water. Mean arterial blood pressure rose by ∼25 mmHg.

  3. In protocol 1, infusions and control of RPP were maintained over three more days. Sodium was retained on all days, resulting in a continuous increase in TBS.

  4. In protocol 2, control of RPP was stopped after day 1. Thus, pressure natriuresis could exert its effect beginning with day 2. Angiotensin II and aldosterone infusions were continued. This prevented the effects of endogenous suppression of the renin-angiotensin-aldosterone system (RAAS), which is caused by increased TBS. No further sodium retention occurred, i.e. TBS remained at the elevated level gained on day 1.

  5. In protocol 3, control of RPP and the infusions were stopped. Thus, pressure natriuresis and RAAS suppression could exert their combined effects. Sodium excretion exceeded sodium intake on day 2. Control level of TBS was regained within 24 h.

  6. It was concluded that when RPP is considerably elevated, pressure natriuresis prevents further increase of TBS in the face of elevated angiotensin II and aldosterone levels. However, pressure natriuresis does not suffice to restore TBS to control. This requires additional endogenous suppression of RAAS.

The quantities of body fluids and electrolytes are controlled within tight boundaries. The control of total body sodium (TBS) is of particular interest, since TBS is a major determinant of long-term mean arterial blood pressure (MABP) (Guyton, 1990a, b, 1991; Cowley, 1992). Variations of sodium intake occur on a large scale. Therefore, TBS needs to be maintained via control of renal sodium excretion. It is clear that various hormonal, neuronal and physical factors impinge on renal sodium excretion. However, the individual importance of each of these control elements for long-term control of TBS has not yet been established.

Arterial pressure is considered to play an important role in the control of sodium excretion and TBS (Guyton, 1990a, b, 1991). It is assumed that an increase of MABP may augment sodium excretion via intrarenal effects of elevated renal perfusion pressure (RPP). This concept is termed ‘pressure natriuresis’. In analogy, decreased RPP may reduce sodium excretion. Hitherto, the intrarenal mechanism underlying pressure natriuresis has not been fully understood (Cowley, 1992).

The specific contribution of pressure natriuresis for control of TBS is confounded by the interference with the renin-angiotensin-aldosterone system (RAAS). Renin release is also controlled by RPP (pressure-dependent renin release) (Hackenthal et al. 1990). Thus, alterations in RPP automatically change the activity of the RAAS. Matters become more complicated by the fact that renin release is additionally controlled by changes in TBS (Seeliger et al. 1999). On the effector side, the RAAS influences MABP by controlling TBS via renal action of angiotensin II and aldosterone, and by the vasoconstrictor action of angiotensin II (Cowley, 1992). Taken together, the controllers of TBS, RAAS and RPP are interwoven and cannot readily be disentangled.

Recent studies (Reinhardt et al. 1994; Boemke et al. 1995; Seeliger et al. 1997) provide evidence that TBS can be controlled independently of pressure natriuresis. In these studies, RPP was reduced by 20 % for four consecutive days. RPP reduction initially decreased sodium and water excretion via pressure-dependent renin release (Boemke et al. 1995). This increases TBS, total body water (TBW) and systemic MABP (Reinhardt et al. 1994). Although pressure natriuresis was prevented by continuous reduction of RPP, 24 h intake-output balances of sodium eventually equilibrated beginning with day 2. This equilibration of 24 h sodium balances at an elevated level of TBS was termed ‘pressure escape’, in analogy to ‘mineralocorticoid escape’ (Reinhardt et al. 1994).

Pressure escape is mainly achieved by endogenous down-regulation of RAAS. When the effects of RAAS suppression are prevented, i.e. angiotensin II and aldosterone levels are held elevated by low-dose infusions, then RPP reduction results in continuous increase of TBS and TBW, and thus, of systemic MABP (Seeliger et al. 1997). Therefore, reduction of RPP plus RAAS ‘clamping’ were used as tools to increase TBS and MABP markedly in the present study. When the reduction of RPP is terminated, but the infusions of angiotensin II and aldosterone are maintained, the individual effect of pressure natriuresis can be studied. The aim of this study was to test whether pressure natriuresis alone may prevent continuous sodium retention, or may even restore TBS to control levels.

METHODS

Balance studies were performed in 27 chronically instrumented female Beagle dogs, about 2 years of age, weighing 11-17 kg. Details of the standardised methods are described in previous papers (Reinhardt et al. 1994; Boemke et al. 1995; Seeliger et al. 1997; Seeliger et al. 1999). On completion of the experimental period, implants were removed and the dogs were given to suitable private owners. The study was approved by the Berlin Government and performed according to the German Animal Protection Law.

The dogs were equipped with a urinary bladder catheter, an inflatable occluder placed around the aorta above the renal arteries, and two aortic catheters. The tip of one was placed just below the renal arteries, the tip of the other one well above. The tubes were exteriorised in the nape region. All operations were performed under aseptic conditions in an operating room. General anaesthesia was induced with methohexital (8 mg (kg body wt)−1i.v.). After endotracheal intubation, anaesthesia was maintained under controlled ventilation with halothane (0.8-1.5 %) and nitrous oxide:oxygen (2:1). The depth of anaesthesia was clinically assessed, i.e. anaesthesia was increased by increasing inspiratory halothane concentration when the dog started to breath spontaneously, moved, or displayed sudden increases in heart rate or blood pressure during surgical procedures. The dogs were allowed at least 3 weeks to recover. Catheter-related infections were prevented by a catheter-restricted antibiotic-lock technique. Daily check-ups for general status, body temperature, body weight, and tests of erythrocyte sedimentation rate ensured that all dogs were healthy. The dogs were housed individually in large kennels (9 m2 basal surface) in an air conditioned, sound protected animal room. For reasons of social well being, at least one more dog in an adjacent kennel accompanied the dog under investigation.

Starting 5 days before the studies, food intake was controlled with regard to daily feeding time (08:30-09:00), completeness of intake, and food composition. The food provided 5.5 mmol Na+, 3.5 mmol K+, and 91 ml water per day and per kg body wt (i.e. 82 mmol Na+, 52 mmol K+, and 1365 ml water per day for a 15 kg dog). Completeness of intake was ensured, and neither additional feeding nor further access to water was allowed.

During the study, the tubes from the dogs were connected to a swivel system that allowed free movement within the 9 m2 kennel. From the swivel, the tubes were led to the adjoining laboratory. Due to separation between laboratory and the sound-protected animal room, the actions necessary to conduct the experiments (urine collection, blood sampling, infusions, reduction of RPP) were taken without attracting the attention of the dogs. Each dog was studied for four consecutive days. A 24 h period lasted from 08:00 through to 08:00 h the following day.

Dogs were randomly assigned to three protocols plus one control protocol. Dogs of the control protocol (control, n = 7) were studied without reduced RPP and with vehicle infusion only.

The following identical conditions were applied on day 1 in protocols 1, 2 and 3: RPP was reduced (rRPP, for details see below), and the RAAS was ‘clamped’ by low-dose infusions of angiotensin II (Hypertensin, Ciba, 4 ng (kg body wt)−1 min−1) and aldosterone (Aldocorten, Ciba, 10 pg (kg body wt)−1 min−1). These conditions were used as tools to reduce sodium excretion, which results in increased TBS, and, in turn, increased systemic MABP (see Fig. 1). This increase in MABP, however, is prevented from acting on renal level due to rRPP.

Figure 1. Impact of pressure natriuresis on urinary Na+ excretion.

Figure 1

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Upper panels depict 24 h mean values of systemic arterial pressure (MABP) and renal perfusion pressure (RPP), as obtained by 1440 1 min values per dog and per 24 h period that lasted from 08:00 to 08:00 the following day. Lower panels depict 24 h urinary excretion of Na+ (UNaV) as a percentage of daily Na+ intake. Values are means ± s.e.m. Dotted horizontal bars represent control group (means ± s.e.m.). Reduction of RPP plus ‘clamping’ of RAAS (low-dose angiotensin II and aldosterone infusions), as applied on day 1 of protocols 1, 2 and 3, reduces Na+ excretion markedly and increases 24 h mean of MABP by ∼25 mmHg. Continuation of these conditions for a further 3 days (protocol 1) results in ongoing reduction of Na+ excretion and continued increase of MABP. With cessation of RPP reduction at the end of day 1 (protocols 2 and 3), RPP immediately increases towards the elevated MABP (RPP = MABP), and hence pressure natriuresis can exert its effect. With continued RAAS ‘clamping’ (protocol 2), Na+ excretion regains control values, and MABP remains on the elevated level gained on day 1. With cessation of RAAS ‘clamping’ (protocol 3), Na+ excretion doubles as compared to control values (day 2), and MABP regains control level. * Significant vs. control; + significant vs. protocol 1, § significant vs. protocol 2; 1 significant vs. day 1, 2 significant vs. day 2, 3 significant vs. day 3, within the respective protocol. For statistics see Methods.

On days 2-4, the conditions differed among protocols. In protocol 1 (n = 6), rRPP as well as angiotensin II and aldosterone infusions were continued. In protocol 2 (n = 7) at the end of day 1, rRPP was stopped (RPP = MABP, see Fig. 1), i.e. increased MABP was allowed to act on the kidneys for days 2-4. However, angiotensin II and aldosterone levels were further held elevated by infusion to counteract endogenous RAAS suppression. In protocol 3 (n = 7), at the end of day 1, rRPP was stopped (RPP = MABP, see Fig. 1). In addition, angiotensin II and aldosterone infusions were also stopped, thus endogenous RAAS suppression could exert its effects.

As previously described (Reinhardt et al. 1994), RPP was reduced and maintained on a pre-set level (80 % of the individual dog's MABP, as had been measured during a separate 24 h control period) by means of an electropneumatic servo-control device connected to the aortic cuff. The applied rRPPs are shown in Fig. 1.

MABP (catheter above the occluder), RPP (catheter below the occluder) and heart rate (HR) were measured continuously and recorded as 1 min averages. By means of a computerised urine collection system, urine was collected during the entire study period. The urine collected during a 24 h period was analysed for Na+ and K+ concentrations. Urine volume was measured by weighing. The difference between 24 h intake and 24 h urinary excretion of water, Na+ and K+ in the control group was considered to be extrarenal loss. As room temperature and moisture were kept constant, and the dogs’ body temperature and physical activity did not change markedly, extrarenal losses in protocols 1-3 are assumed to equal those of controls. Hence, individual 24 h balances were calculated as differences between the excretion in the control group and the individual dog's excretion on the respective days in protocols 1-3. Individual cumulative balances were calculated by summing up the 24 h balance values over the four consecutive study days. Changes in cumulative balances reflect changes in TBS, total body potassium (TBP) and total body water (TBW).

Every 4 h (09:00, 13:00, 17:00, 21:00, 01:00, 05:00) blood samples were taken via an arterial line. The blood withdrawn was replaced by an equal amount of stored blood collected from the respective dog 2 weeks in advance. In each sample concentrations of Na+ (PNa), K+ (PK), protein (PProt), atrial natriuretic peptide (ANP), and aldosterone (PAC) were measured, as well as plasma renin activity (PRA), haematocrit (Hct) and osmolality (Posmol), where P represents plasma. Hormones were analysed with commercial radio-immuno assays. Glomerular filtration rate (GFR) was measured by exogenous creatinine clearance. For details see Reinhardt et al. (1994).

In each dog, 24 h means of plasma parameters (out of the six plasma samples collected during the respective 24 h period) and 24 h means of MABP, HR and RPP (out of the 1440 1 min records) were obtained. These individual 24 h means were averaged within the respective protocol and day. Accordingly, the individual 24 h excretion values and cumulative balances were averaged within the respective protocol and day.

Statistical comparisons were made using the Number Cruncher Statistical Software 6.0 (J. L. Hintze, Kaysville, UT, USA). Differences among the protocols were assessed by Student's unpaired t test with Bonferroni's adjustment for multiple comparisons (P < 0.05/m, where m is the number of comparisons between protocols). Differences between mean 24 h values of the distinct days within the protocols were assessed by GLM ANOVA for repeated measurements, followed by Duncan's multiple comparison test (P < 0.05). Data are presented as means ± s.e.m.

RESULTS

In the control group, average 24 h MABP (=RPP) was 117 ± 3 mmHg; average 24 h urinary excretion ratios were: urine volume 88 ± 2 % of water intake, Na+ excretion 91 ± 5 % of intake, and K+ excretion 84 ± 4 % of intake.

Reduction of RPP plus low dose angiotensin II and aldosterone infusions, as were applied on day 1 of protocols 1, 2 and 3, reduced Na+ excretion markedly (Fig. 1), thus, TBS increased by ∼4.4 mmol (kg body wt)−1 (Fig. 2). Urine volume decreased as well, and hence TBW increased (Table 1). MABP increased during the course of this day yielding 24 h mean values of ∼142 mmHg, i.e. ∼25 mmHg above control level (Fig. 1).

Figure 2. Contribution of pressure natriuresis to control of total body sodium.

Figure 2

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Changes of total body sodium (ΔTBS, obtained by cumulative Na+ balances) are shown. Values are means ± s.e.m. (for points with missing error bar, s.e.m. smaller than symbol size). For statistics see Methods; for significance symbols see Legend of Fig. 1. Reduction of RPP plus ‘clamping’ of RAAS (low-dose angiotensin II and aldosterone infusions), as applied on day 1 of protocols 1, 2 and 3, increases TBS by ∼4.4 mmol Na+ (kg body wt)−1. Continuation of these conditions for a further 3 days (protocol 1) results in ongoing increase of TBS. With cessation of RPP reduction at the end of day 1 (protocols 2 and 3), RPP immediately increases toward the elevated MABP, and hence pressure natriuresis can exert its effect. With continued RAAS ‘clamping’ (protocol 2), TBS does not further increase, yet remains on the elevated level gained on day 1. TBS returns to control level only when RAAS ‘clamping’ is also stopped (protocol 3).

Table 1.

Parameters of total body water, total body potassium, heart rate and plasma hormone concentrations

Day 1 Day 2 Day 3 Day 4
ΔTBW Prot 1 28.3 ± 3.2* 48.5 ± 7.2* 63.8 ± 12.1* 1 89.0 ± 17.0* 1,2,3
(ml kg−1) Prot 2 29.9 ± 2.2* 25.1 ± 6.0 *† 23.0 ± 6.4 *† 24.6 ± 7.1 *†
Prot 3 28.9 ± 2.1* −4.3 ± 3.4 †§ 1 1.0 ± 3.1 †§ 1 3.7 ± 4.1 †§ 1
ΔTBP Prot 1 0.12 ± 0.20 −0.63 ± 0.32 1 −1.33 ± 0.36* 1,2 −1.61 ± 0.46* 1,2
(mmol kg−1) Prot 2 0.33 ± 0.37 −1.03 ± 0.45 1 −1.98 ± 0.43* 1,2 −2.22 ± 0.37* 1,2
Prot 3 −0.21 ± 0.22 −0.61 ± 0.16* −0.22 ± 0.22§ −0.38 ± 0.31†§
HR Control 94.2 ± 4.9 97.4 ± 6.3 98.1 ± 4.1 98.0 ± 4.7
(beats min−1) Prot 1 78.2 ± 7.0* 66.6 ± 8.8* 1 63.2 ± 9.1* 1 65.7 ± 8.1* 1
Prot 2 80.5 ± 5.1* 76.1 ± 5.5* 1 73.9 ± 4.5* 1 74.9 ± 4.8* 1
Prot 3 80.9 ± 4.5* 80.2 ± 4.4* 84.4 ± 4.6 *† 89.3 ± 5.5 †§ 1,2
PRA Control 2.71 ± 0.30 2.98 ± 0.38 2.91 ± 0.30 2.93 ± 0.28
(ng Ang I h−1 ml−1) Prot 1 2.29 ± 0.72 1.43 ± 0.56 0.34 ± 0.16* 1 0.31 ± 0.13* 1,2
Prot 2 2.22 ± 0.43 0.22 ± 0.05*† 1 0.17 ± 0.03* 1 0.16 ± 0.03* 1
Prot 3 2.45 ± 0.40 1.40 ± 0.32*§ 1 1.95 ± 0.25*†§ 2.45 ± 0.34 †§ 2
PAC Control 76 ± 9 85 ± 7 86 ± 11 69 ± 9
(pg ml−1) Prot 1 359 ± 24* 380 ± 34* 364 ± 35* 339 ± 46*
Prot 2 330 ± 27* 306 ± 21* 310 ± 23* 328 ± 24*
Prot 3 352 ± 45* 65 ± 9 †§ 1 51 ± 13 *†§ 1 49 ± 12 †§ 1
ANP Control 43 ± 2 44 ± 2 39 ± 1 41 ± 3
(pg ml−1) Prot 1 97 ± 9* 133 ± 18* 1 173 ± 18* 1,2 203 ± 17* 1,2,3
Prot 2 101 ± 7* 148 ± 13* 1 170 ± 20* 1 163 ± 20* 1
Prot 3 93 ± 6* 85 ± 5 *†§ 66 ± 5 *†§ 1,2 57 ± 4 *†§ 1,2
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Changes of total body water and total body potassium (ΔTBW and ΔTBP, obtained by cumulative balances) at the end of the respective day; 24 h mean values of heart rate (HR), and 24 h mean values of plasma parameters (obtained by 6 plasma samples per day and dog): plasma renin activity (PRA), plasma concentrations of aldosterone (PAC) and atrial natriuretic peptide (ANP). Values are means ± s.e.m.

*

Significant vs. Control

†

significant vs. protocol 1

§

significant vs. protocol 2;−1 significant vs. day 1, 2 significant vs. day 2, 3significant vs. day 3, within the respective protocol. For protocols and statistics see Methods.

In protocol 1, rRPP plus infusions were continued on days 2-4, and Na+ excretion was reduced on all days (Fig. 1). Thus, TBS continuously increased, reaching a surplus of ∼13.0 mmol (kg body wt)−1 until the end of day 4 (Fig. 2). Likewise, TBW continued to increase (Table 1). MABP rose continuously, reaching a 24 h mean of ∼162 mmHg on day 4 (Fig. 1).

In protocol 2, rRPP was stopped at the end of day 1, whereas angiotensin II and aldosterone were continuously administered. RPP immediately increased toward the elevated MABP (RPP = MABP). Consequently, elevated pressure could impinge on renal excretion throughout days 2-4. Sodium excretion regained control excretion on day 2. Twenty-four-hour sodium balances of days 2-4 were equilibrated (Fig. 1), and thus TBS neither increased nor decreased significantly, i.e. TBS remained on the elevated level obtained on day 1 (Fig. 2). At the end of day 4, surplus TBS amounted to ∼3.9 mmol (kg body wt)−1. Likewise, TBW did not change, but remained elevated (Table 1). MABP and RPP did not change. Their 24 h means amounted to ∼142 mmHg on day 4 (Fig. 1).

In protocol 3, rRPP as well as angiotensin II and aldosterone infusions were stopped at the end of day 1. Again, RPP immediately increased, and RPP equalled MABP throughout the days 2-4. Sodium excretion increased markedly on day 2; it was doubled as compared with control excretion (Fig. 1). Due to this negative 24 h balance, TBS regained control level within 24 h (Fig. 2). On days 3 and 4, 24 h sodium balances were equilibrated again, and thus TBS remained on control level. Similarly, TBW regained control level within 24 h (Table 1). During the course of day 2, MABP and RPP decreased, yielding a 24 h mean of ∼124 mmHg. On days 3 and 4, MABP and RPP were on control level again (Fig. 1).

HR decreased on day 1 in protocols 1, 2 and 3 (Table 1). HR decreased further in protocols 1 and 2, on day 4 reaching ∼67 % of control in protocol 1, and ∼77 % in protocol 2. In protocol 3, HR regained control values on day 4. GFR was unchanged in protocols 1, 2 and 3 (data not shown).

Plasma renin activity (PRA) was unchanged on day 1 in protocols 1, 2 and 3 (Table 1). In protocol 1, PRA decreased stepwise on the following days and on day 4 was very low. In protocol 2, a sharp decrease of PRA occurred on day 2, and on the following days PRA remained very low. In protocol 3, PRA was transiently lowered (days 2 and 3), yet regained control values on day 4. By means of continuous aldosterone infusion, PAC was held elevated on day 1 in protocols 1, 2 and 3, as well as on days 2-4 in protocols 1 and 2 (Table 1). In protocol 3, the infusion was stopped at the end of day 1, and PAC decreased below control level. Atrial natriuretic peptide (ANP) increased on day 1 in protocols 1, 2 and 3 (Table 1). In protocol 1, ANP continued to rise throughout the study. In protocol 2, ANP increased again on day 2, yet remained at this level on days 3 and 4. In protocol 3, ANP decreased stepwise on days 2-4, but it finally remained higher than control even on day 4.

Total body potassium (TBP) did not change on day 1 in protocols 1, 2 and 3 (Table 1), yet plasma potassium (PK) increased significantly as compared with control (4.04 ± 0.06 vs. 3.88 ± 0.06 mmol l−1). TBP decreased in protocols 1 and 2 on the following days (Table 1), and PK decreased, on day 4 reaching 3.23 ± 0.13 in protocol 1, and 2.79 ± 0.04 in protocol 2. Plasma sodium (PNa) (controls: 145.6 ± 1.4 mmol l−1), Posmol (301.9 ± 1.1 mosmol kg−1), PProt (5.5 ± 0.2 g (100 ml)−1), and Hct (37.8 ± 1.9 %) were unchanged in protocols 2 and 3. In protocol 1, PNa and Posmol increased significantly, reaching 149.1 ± 1.2 mmol l−1 and 307.6 ± 2.5 mosmol kg−1, respectively, while PProt and Hct decreased significantly, reaching 4.9 ± 0.2 g (100 ml)−1 and 33.0 ± 1.8 % on day 4, respectively.

DISCUSSION

The present study was performed in freely moving dogs to elucidate the role of pressure natriuresis in long-term control of TBS. Special care was taken to distinguish between effects caused by pressure natriuresis and those exerted by endogenous changes of the RAAS. Based upon the results of a previous study (Seeliger et al. 1997), reduction of RPP plus low-dose infusions of angiotensin II and aldosterone were used as tools to increase TBS and MABP. Within the first 24 h, TBS was augmented by ∼4.4 mmol (kg body wt)−1, and MABP rose by ∼25 mmHg. In protocol 2, the question was addressed whether pressure natriuresis can compensate for sodium retention, if the considerable pressure increase is permitted to act on the kidneys. To this end, the reduction in RPP was terminated at the end of day 1. However, the low-dose infusions of angiotensin II and aldosterone were maintained to counteract endogenous suppression of the RAAS. The results show that pressure natriuresis facilitates Na+ excretion: 24 h Na+ balances equilibrate, and thus there is no further increase in TBS. On the other hand, TBS did not return to normal, but remained on the elevated level gained on day 1. Hence, elevation of RPP by about 25 mmHg accomplished an ‘escape’. The surplus of TBS is not corrected, and as long as TBS is augmented, MABP remains elevated.

Comparison with the results of protocol 1 reveals, that pressure natriuresis is a powerful compensatory mechanism in TBS control: continuation of servocontrolled reduction in RPP plus angiotensin II and aldosterone infusions results in a steady increase of TBS and MABP. Apparently, pressure natriuresis prevents further Na+ retention. This is in line with results of Hall and colleagues, who performed studies on ‘mineralocorticoid escape’ (Hall et al. 1984b) and on ‘angiotensin II escape’ (Hall et al. 1984a) in dogs. In these studies, increases in RPP were induced by Na+ retention. When this RPP increase was counteracted by servocontrol, escape did not occur. These studies, however, provided conflicting results regarding TBS after cessation of RPP servocontrol. In one study, TBS remained elevated (Hall et al. 1984b), but TBS decreased below control level in the other study (Hall et al. 1984a).

The relationship between MABP and Na+ excretion has been depicted as a ‘chronic renal function curve’. These curves were primarily intended to analyse pressure control during steady-state conditions (Guyton, 1990a, b; Cowley, 1992; Hall et al. 1996). The often-used y-axis label ‘Na+ intake equals Na+ output, times normal’ indicates that 24 h balances are equilibrated at each point of the renal function curves. Therefore, the curves do not provide an immediate answer to the question of whether TBS is changed or not. For instance, when Na+ excretion is primarily altered, e.g. due to elevated levels of angiotensin II or aldosterone, the ‘renal function curve’ is shifted towards higher MABP (Guyton, 1990a,b; Hall et al. 1996). In the steady state, MABP is elevated, while Na+ excretion is not increased. Thus, it was assumed that the mechanism of pressure natriuresis was ‘reset’ by antinatriuretic hormones (Guyton, 1990a, b; Hall et al. 1996). This resetting of pressure natriuresis would necessitate increased MABP to maintain Na+ balance (Hall et al. 1996). Since 24 h Na+ balances are depicted as being equilibrated, neither the source of initial increase of MABP nor the cause behind sustained elevation of MABP is obvious from the ‘renal function curves’. Analysis of the sequence of Na+ balances (see Fig. 2) reveals the following: initial elevation of MABP is a consequence of positive 24 h Na+ balance, i.e. the surplus of TBS gained during day 1. After this transient time, 24 h balances equilibrate again, while the TBS surplus remains. Thus, the lasting TBS surplus is the reason for sustained elevation of MABP, and the new steady state represents a completed escape. As shown by protocol 2, pressure natriuresis is pivotal in accomplishing this new steady state. On the other hand, pressure natriuresis does not bring TBS back to normal. This can be explained by a resetting of pressure natriuresis. A resetting would imply that the mechanism of pressure natriuresis is active at any pressure, an assumption that is not unequivocal. For instance, a 20 % reduction in RPP does not decrease Na+ excretion via the mechanism of pressure natriuresis, but by stimulating pressure-dependent renin release (Boemke et al. 1995). Moreover, the diurnal variations of Na+ excretion mirror the time courses of Na+ intake. These time patterns, however, are unrelated to pressure changes. Obviously, Na+ excretion varies without equivalent pressure changes. Vice versa, moderate pressure changes do not change Na+ excretion (Palm et al. 1992; Reinhardt et al. 1996). A possible explanation is that pressure natriuresis is only functional when MABP is significantly elevated over longer time periods. In this case, pressure natriuresis becomes active as a compensating mechanism to prevent further Na+ accumulation and MABP increase. Nevertheless, pressure natriuresis fails to fully correct TBS and MABP. Clearly, further studies are needed to clarify if this hypothesis is correct.

Augmented TBS suppresses renin release (Seeliger et al. 1999). Furthermore, excess TBS also inhibits aldosterone secretion, even when renin is elevated (Reinhardt et al. 1994). Suppression of the RAAS is another major compensatory mechanism in TBS control (Seeliger et al. 1997). The common effect of two compensatory mechanisms, RAAS suppression plus pressure natriuresis, was studied in protocol 3: reduction of RPP was terminated, and angiotensin II and aldosterone infusions were stopped. This resulted in a striking increase of Na+ excretion. Within 24 h, the amount of Na+ ingested on this day is excreted along with the amount retained on day 1. In other words, within 24 h the control level of TBS is regained and MABP returns to normal. It is concluded that the combined effect of pressure natriuresis and RAAS downregulation is required to restore control values of TBS and MABP.

Angiotensin II also suppresses renin release (Hackenthal et al. 1990). On day 1 of protocols 1, 2 and 3 (see Table 1), this inhibition of renin release is counterbalanced by reduction of RPP (pressure-dependent renin release). During the following 3 days of protocol 1, PRA decreases gradually, most probably due to the continuous increase in TBS. In contrast to the first protocol, in protocols 2 and 3, termination of RPP reduction promptly blunted renin release. When this pressure effect is combined with elevated angiotensin II and augmented TBS (days 2-4 in protocol 2), then PRA is almost fully suppressed. It should be noted, that this decrease of PRA could not exert an effect, since angiotensin II was ‘clamped’ by infusion. Conversely, when angiotensin II infusion is stopped in protocol 3, the decrease of PRA elicits an effect via decreased angiotensin II. With the resulting normalisation of TBS, PRA regains control level again.

The present study elucidates the role of pressure natriuresis for long-term control of TBS during considerable elevation of RPP. Previous studies from this laboratory (Reinhardt et al. 1994; Boemke et al. 1995; Seeliger et al. 1997) contributed to clarifying the role of reduced RPP. Since the former studies were performed under the same standardised conditions as the present experiments, the compensatory potencies of RAAS suppression and pressure natriuresis in counteracting ongoing Na+ retention can be directly compared. The quantitative effects can be estimated by comparison between the surpluses in TBS. The quantitative effect of pressure natriuresis is the difference in surplus TBS as caused by continuous reduction of RPP plus angiotensin II and aldosterone infusion in protocol 1 (∼13 mmol Na+ kg−1 at the end of day 4, see Fig. 2) and the remaining surplus of TBS after release of RPP reduction in protocol 2 (∼3.9 mmol kg−1 at the end of day 4). The magnitude of this compensatory effect is comparable to that exerted by endogenous suppression of RAAS. The previous study with continuous reduction of RPP, yet without preventing RAAS suppression, revealed that the remaining TBS surplus after completion of pressure escape amounted to ∼3.5 mmol kg−1 (Reinhardt et al. 1994). Thus, both compensatory mechanisms, endogenous inhibition of RAAS and pressure natriuresis, possess similar potency. It is conceivable, however, that the quantitative contribution of RAAS would increase if the dogs were kept on a lower Na+ intake.

The major portion of compensation during protocol 2 was achieved by pressure natriuresis. The major part of the compensation during pressure escape was brought about by suppression of RAAS. It should be noted, however, that in either case a small part of compensation was achieved by other mechanisms facilitating Na+ excretion. This is concluded from results of protocol 1: 24 h Na+ excretion, although never equalling Na+ intake, increased slightly during the study (see Fig. 1), and thus daily Na+ accumulation was less on day 4 as compared with day 1 (Fig. 2). In other words, continued Na+-retaining effect is partially compensated for. This has been referred to as partial escape (Seeliger et al. 1997). The effect is accomplished by the entity of all Na+-eliminating factors that do not act via RAAS inhibition or a pressure natriuresis mechanism. Various hormones, mediators, and physical factors are suggested to possess Na+-eliminating potency, e.g. ANP, urodilatin, kinines, nitric oxide, prostaglandines, and colloid osmotic pressure. In the face of the striking TBS increase, these factors are presumably maximally stimulated. Indeed, ANP increased dramatically (see Table 1). Elevated systemic arterial pressure probably also stimulated Na+-eliminating mechanisms, e.g. via carotid and aortic baroreceptors. Inhibition of renal sympathetic nerve activity by these receptors reduces tubular Na+ resorption (Lohmeier et al. 2000). It should be noted, however, that even the sum of all these factors does not prevent continuous Na+ and water retention. Hence, the potency of these Na+-eliminating factors is meagre.

Atrial stretch is the major determinant of ANP secretion. It is well known that circulating ANP levels rise with physiological increases in atrial wall tension, in particular by volume expansion (Ruskoaho, 1992). In the present study, ANP took on higher values in parallel with TBW on day 1 in protocols 1, 2 and 3, as well as throughout the entire protocol 1. This suggests that the TBW increase and the resulting intravascular volume expansion caused the ANP augmentation. On the other hand, ANP did not completely mirror changes in TBW (see Table 1). In protocol 2, although TBW did not increase further on day 2, ANP continued to increase on this day. In protocol 3, ANP remained elevated throughout the study, although TBW regained control level on day 2. If we assume that changes of TBW result in parallel changes of intravascular volume, then other stimuli must have contributed to ANP secretion under these conditions. Various factors modulate ANP secretion, e.g. catecholamines, angiotensin II, endothelin, NO, osmolality and oxygen tension (for review see Ruskoaho, 1992; Ruskoaho et al. 1997). Whether one of these factors was involved in the observed TBW-independent changes of ANP remains to be studied.

In summary, augmented TBS elevates MABP. Thus, TBS is a major factor in long-term pressure control. Vice versa, RPP has differential effects on Na+ excretion: significant pressure increase facilitates Na+ excretion via pressure natriuresis, whereas pressure reduction reduces excretion via stimulation of RAAS. Furthermore, long-term control of TBS cannot be achieved solely by either pressure natriuresis or hormonal control. Long-term maintenance of TBS is only achieved when both these major controllers are functional.

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft. We thank Klaus Dannenberg, Benno Nafz and Rainer Mohnhaupt for maintenance of the laboratory equipment, Daniela Bayerl, Sabine Molling and Christopher Pfaff for technical assistance and Christina Kasprzak and Jeanette Wagner for animal care.

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