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1 Department of Medical Physiology, University of Copenhagen, DK-2200 Copenhagen; and 2 Department of Physiology and Pharmacology, University of Southern Denmark, Odense, DK-5000 Odense, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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.
Saline was
infused intravenously for 90 min to normal, sodium-replete conscious
dogs at three different rates (6, 20, and 30 µmol · kg
1 · min1)
as hypertonic solutions (HyperLoad-6, HyperLoad-20, and HyperLoad-30, respectively) or as isotonic solutions (IsoLoad-6, IsoLoad-20, and
IsoLoad-30, respectively). Mean arterial blood pressure did not change
with any infusion of 6 or 20 µmol · kg1 · min1.
During HyperLoad-6, plasma vasopressin increased by 30%, although the
increase in plasma osmolality (1.0 mosmol/kg) was insignificant. During
HyperLoad-20, plasma ANG II decreased from 14 ± 2 to 7 ± 2 pg/ml
and sodium excretion increased markedly (2.3 ± 0.8 to 19 ± 8 µmol/min), whereas glomerular filtration rate (GFR) remained constant. IsoLoad-20 decreased plasma ANG II similarly (13 ± 3 to 7 ± 1 pg/ml) concomitant with an increase in GFR and a smaller increase
in sodium excretion (1.9 ± 1.0 to 11 ± 6 µmol/min). HyperLoad-30 and IsoLoad-30 increased mean arterial blood pressure by 6-7 mmHg and decreased plasma ANG II to ~6 pg/ml, whereas sodium excretion increased to ~60 µmol/min. The data demonstrate that, during slow sodium loading, the rate of excretion of sodium may increase 10-fold without changes in mean arterial blood pressure and GFR and suggest that the increase may be mediated by a decrease in plasma ANG II.
Furthermore, the vasopressin system may respond to changes in plasma
osmolality undetectable by conventional osmometry.
angiotensin II; volume expansion; vasopressin; blood pressure; natriuresis.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE RELATIVE IMPORTANCE of the humoral, hemodynamic, and nervous mechanisms in the regulation of renal sodium excretion is still controversial. The relative roles of the arterial blood pressure and the renin-angiotensin-aldosterone system in providing sodium homeostasis are particularly complex. Recently, we demonstrated (4) that a sodium load simulating daily sodium intake induced natriuresis concomitant with a decrease in plasma ANG II level and a small, but significant, increase in arterial blood pressure. Under these circumstances, the natriuresis may be explained by the decrease in plasma ANG II level and by the increase in arterial blood pressure. Sodium loading was also performed during normotensive ANG II clamping, i.e., a constant infusion of ANG II sufficient to normalize arterial blood pressure during control conditions. Under these conditions, >90% of the natriuretic response to sodium loading was blocked, indicating a pivotal role of ANG II in the control of renal sodium excretion. However, the procedure of sodium loading still increased arterial blood pressure. Different methods may be used to isolate the effect of an increase in renal perfusion pressure, including aortic cuffs (22) and pharmacological pressure control (1). In this study we chose to infuse different sodium loads at rates that are too small to change arterial blood pressure and to measure the concomitant endocrine and renal excretory changes. In this way it might be possible to separate the effects of humoral factors from those of changes in arterial blood pressure without interfering with intrarenal hemodynamics or constricting the renal artery. To our knowledge the responses to such small, slow sodium loads in conscious dogs have not previously been reported.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
The experiments were performed in conscious female Beagle dogs weighing 11.5-16 kg. The dogs were kept on a fixed diet (Special Diets Services, Witham, UK) and received one meal a day at around 1400. Mean daily sodium intake was 2.2 ± 0.1 mmol/kg body wt (mean ± SE). The dogs had free access to tap water. Before the study, several surgical interventions were performed as described in the preceding paper (4). The dogs were trained for several months before the experiments, which were approved by the Danish Animal Experiments Inspectorate.Experimental Protocol
The same six dogs were used for all experiments, and in the last two infusion series (see below) one more dog was included. In each dog, experiments were performed at intervals of >1 wk. At midnight before the experiment, an electric valve controlled by a timer interrupted the water supply. On the experimental day, the dog was transferred to the laboratory and prepared for study as previously described (4). Briefly, catheters were placed in a central vein, in a carotid artery, and in the bladder. After a 30-min control period, isotonic or hypertonic salt loading was initiated and continued for 90 min (t = 120 min) followed by a 30-min recovery period.The first sample of arterial blood was obtained at t = 
5
min; subsequent samples were obtained 25 min into each sampling period.
Samples of 1 ml drawn at t = 5 min, t = 55 min,
and t = 85 min were used to measure the plasma creatinine,
whereas electrolyte, ANG II, vasopressin, and creatinine levels were
measured from 15-ml samples obtained at t = 25 min, t = 115 min, and t = 145 min.
The renal, hemodynamic, and humoral responses to intravenous sodium loads of different magnitude were investigated in seven experimental series of six or seven experiments.
IsoLoad-6. An intravenous infusion of isotonic NaCl solution
(154 mmol/l) was initiated at t = 30 min and continued for 90 min at a rate of 6 µmol · kg1 · min1,
i.e., at a flow rate of 0.039 ml · kg1 · min1.
Saline loading was followed by a 30-min recovery period (n = 6).
HyperLoad-6. This experimental series was identical to the
IsoLoad-6 series, except that the same sodium load (6 µmol · kg1 · min1
NaCl) was administered as a hypertonic (2 mol/l NaCl) solution. Thus
the infusion rate was 0.003 ml · kg1 · min1
(n = 6).
IsoLoad-20. The IsoLoad-20 series was identical to the
IsoLoad-6 series, except that isotonic NaCl solution (154 mmol/l) was infused at a rate of 20 µmol · kg1 · min1,
corresponding to 0.13 ml · kg1 · min1
(n = 6).
HyperLoad-20. The sodium load of 20 µmol · kg1 · min1
NaCl was administered as a hypertonic (2 mol/l NaCl) solution from
t = 30 to 120 min. The rate of infusion was 0.01 ml · kg1 · min1
(n = 6).
IsoLoad-30. IsoLoad-30 involved infusion of isotonic NaCl
solution (154 mmol/l) for 90 min at a rate of 30 µmol · kg1 · min1,
i.e., at a rate of 0.195 ml · kg1 · min1
(n = 7).
HyperLoad-30. A sodium load of 30 µmol · kg1 · min1
NaCl was administered as a hypertonic (2 mol/l NaCl) solution from
t = 30 to 120 min. Thus the rate of infusion was 0.015 ml · kg1 · min1
(n = 7).
Arterial blood pressure was measured continuously by a pressure transducer (Statham P50, Gould) connected to a patient monitor (Dialogue 2000, Danica Elektronik, Rødovre, Denmark). This provided analog-to-digital conversion at a rate of 300 Hz on the basis of a 7-s time window and calculation of mean arterial blood pressure. Heart rate was calculated from the electrocardiogram signal. Data were sampled from the monitor every 10 s by computer and subsequently averaged over 30-min periods.
Analyses
The concentrations of sodium and potassium ions in plasma and urine were measured by flame photometry (model 243, Instrumentation Laboratory). Plasma and urine osmolality was determined by freezing-point depression (model 3D3, Advanced Instruments, Needham Heights, MA). Plasma protein concentration was measured by a refractometer (model T2-NE, Atago, Tokyo, Japan). Concentrations of creatinine in urine and plasma were measured by the Jaffé reaction, as described by Bonsnes and Taussky (5).The analyses of hormone levels in plasma were performed by radioimmunoassay after extraction as previously described (10).
Immunoreactivity of vasopressin in extracts of plasma was measured using an antibody (AB3096) produced in this laboratory. The antibody and the method have been described earlier (4, 11). The detection limit was 0.2 pg/ml, and the mean recovery of unlabeled vasopressin was 68%. Intra- and interassay coefficients of variation were <8%.
To determine ANG II immunoreactivity in plasma, a specific antibody (Ab-5-030682) was used as described earlier (4). Detection limit was 1.4 pg/ml, and the mean recovery of unlabeled ANG II was 88%. Intraassay coefficient of variation was 5%, and interassay coefficient of variation was 7%.
Statistics
Data are presented as means ± SE. The results were evaluated by one-way ANOVA for repeated measurements within and between groups. Possible inhomogeneity of variance was assessed by use of Levene's test. When inhomogeneity was present, the data were logarithmically transformed before analysis. If the results of the ANOVA were significant (P < 0.05), all differences between means were investigated systematically by Newman-Keuls test. P values smaller than 0.05 were considered to indicate significance.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Systemic Hemodynamics
In all series, low and constant control levels of mean arterial blood pressure and heart rate were observed. During and after administration of isotonic and hypertonic saline at rates of 6 and 20 µmol · kg1 · min1,
mean arterial blood pressure and heart rate remained unchanged (Table
1). HyperLoad-30 increased mean arterial
blood pressure but did not change heart rate. IsoLoad-30 increased mean
arterial blood pressure to similar values while heart rate was
elevated, indicating activity of the Bainbridge reflex (Table 1).
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Plasma Electrolytes, Osmolality, and Protein Concentration
During HyperLoad-6 and IsoLoad-6, no significant changes occurred in plasma sodium and potassium concentrations or in plasma osmolality (Table 2 and Fig. 1). In both series, plasma protein concentration exhibited small, but significant, decreases (Table 2). HyperLoad-20 increased plasma sodium concentration by 1% and plasma osmolality by 6 mosmol/kg, whereas HyperLoad-30 increased plasma sodium by 4 mmol/l and plasma osmolality by 7 mosmol/kg (Table 2 and Fig. 1). IsoLoad-20 and IsoLoad-30 decreased plasma protein concentration without changes in plasma sodium, plasma potassium, and plasma osmolality.
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Hormones
During HyperLoad-6 experiments, plasma vasopressin was increased by 30% (from 0.84 ± 0.05 to 1.11 ± 0.09 pg/ml) despite the absence of measurable changes in plasma osmolality (Fig. 1). The larger, and measurable, osmotic stimuli occurring during the HyperLoad-20 and HyperLoad-30 series further augmented plasma vasopressin to 3.21 ± 0.22 and 4.01 ± 0.46 pg/ml, respectively. In all hypertonic series, plasma vasopressin remained elevated in the recovery period. In IsoLoad-6, -20, and -30 series, plasma vasopressin levels were unchanged throughout the experiment (Fig. 1).During HyperLoad-6 and IsoLoad-6 experiments, no changes were observed
in the plasma levels of ANG II (Fig. 2). In
HyperLoad-20 and IsoLoad-20 series, plasma ANG II decreased to 50% of
control (14.2 ± 2.2 to 7.2 ± 1.9 pg/ml and 12.8 ± 1.7 to 6.0 ± 0.6 pg/ml, respectively) and remained at this level throughout the
experiments. When sodium loading was given at the rate of 30 µmol · kg1 · min1
(HyperLoad-30 and IsoLoad-30), there was a tendency toward larger decreases in plasma ANG II levels (Fig. 2).
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Renal Variables
Creatinine clearance was used as a measure of GFR (Table 3). In the HyperLoad-6 and HyperLoad-20 series, mean GFR values were remarkably steady at ~40 ml/min and no trend toward a change was observed. During IsoLoad-6 experiments, GFR exhibited a transient increase, and, in the IsoLoad-20 series, the increase in GFR persisted for the remainder of the experiment (Table 3). Administration of HyperLoad-30 and IsoLoad-30 increased GFR by similar amounts, i.e., by 15 and 13%, respectively (Table 3).
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Urine flows and free water clearances were stable at ~0.15 and
0.35 ml/min, respectively, during and after sodium and water loads of HyperLoad-6 and IsoLoad-6 (Fig. 1). HyperLoad-20 decreased free water clearance from 0.34 ± 0.02 to 0.47 ± 0.05 ml/min, whereas no changes were observed in urine flow. IsoLoad-20
increased urine flow from 0.12 ± 0.02 to 0.20 ± 0.04 ml/min
concomitant with a small decrease in free water clearance (Fig. 1). The
large salt load (HyperLoad-30) markedly reduced free water clearance concurrent with a substantial increase in plasma vasopressin levels. However, urine flow in this series was elevated from 0.11 ± 0.02 to
0.23 ± 0.04 ml/min and further to 0.37 ± 0.08 ml/min during recovery period, because the osmolar clearance increased more than free
water clearance fell. IsoLoad-30 augmented urine flow some fivefold
(0.12 ± 0.01 to 0.58 ± 0.17 ml/min), whereas free water clearance
exhibited a small transient decrease (Fig. 1).
The effects of sodium and water loading on renal sodium excretion are
shown in Fig. 2B. The overall pattern shows a clear-cut dose-response relationship within the range of 6-30
µmol · kg1 · min1.
No changes were observed during infusion of HyperLoad-6 and IsoLoad-6,
but sodium excretion was elevated above control level in the recovery
period of HyperLoad-6 series. During the HyperLoad-20 and IsoLoad-20
series, renal sodium excretion increased to 19 ± 8 and 11 ± 6 µmol/min, respectively, and was further augmented in the
recovery period (26 ± 9 and 14 ± 6 µmol/min, respectively). Sodium excretion during the HyperLoad-30 and IsoLoad-30 series exhibited large, but similar, increases during the infusion periods (61 ± 13 and 65 ± 17 µmol/min, respectively). In contrast, during the
recovery period, sodium excretion rate continued to increase in the
HyperLoad-30 series (to 83 ± 19 µmol/min), whereas it leveled off
in the IsoLoad-30 series (63 ± 16 µmol/min). Comparing the results
of hypertonic infusions with those of isotonic infusions, there was a
trend toward higher levels of sodium excretion in the recovery period
in the hypertonic series. In most series, GFR did not increase
persistently. In other series, the relative changes in GFR were much
smaller than the corresponding changes in the rates of excretion of
sodium. Therefore, the pattern of changes in fractional sodium
excretion was very similar to that of absolute sodium excretion (Table
3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to identify the relative importance of changes in arterial blood pressure and other natriuretic factors by measuring the response to sodium loads, which were too small to change arterial blood pressure. These circumstances were achieved by administration over 90 min of sodium loads increasing from 25% of daily sodium intake. With the use of this approach, under highly standardized conditions it was possible to increase renal sodium excretion by ~10-fold without any change in mean arterial blood pressure, heart rate, or GFR.
In the control situations, mean arterial blood pressure was stable,
averaging 108 mmHg (Table 1). A threshold for blood pressure elevation
by saline infusion was apparent as administration of 6 and 20 µmol · kg1 · min1
did not change mean arterial blood pressure, and infusion of 30 µmol · kg1 · min1
increased mean arterial blood pressure by 6-7 mmHg. Over 90 min, the two highest rates correspond to sodium loads of 80 and 125% of
daily sodium intake. The effects on mean arterial blood pressure appear
to be dependent on the infusion rate of sodium rather than the total
amount of sodium infused. This follows from the finding that mean
arterial blood pressure did not change at all during the full 90 min of
HyperLoad-20 or IsoLoad-20 but increased significantly well within the
first 60 min of infusion in the HyperLoad-30 and IsoLoad-30 series. The
amounts of sodium infused within these time frames are identical. So
the blood pressure of these conscious dogs was increased by infusion of
NaCl at rates larger than a threshold, somewhere between 20 and 30 µmol · kg1 · min1.
Other reports of the effects of acute sodium loading on mean arterial
blood pressure in dogs have not provided comparable results. Cowley et
al. (7) showed that a 10-min volume expansion with 400 ml isotonic
saline in conscious dogs, corresponding to ~410 µmol · kg1 · min1,
increased mean arterial blood pressure by 6 mmHg, whereas the same load
for 30 min (~140
µmol · kg1 · min1)
did not change mean arterial blood pressure (8). Kaczmarczyk et al.
(15) reported an increase of 10 mmHg in mean arterial blood pressure
after infusion of 150 µmol · kg1 · min1
of sodium chloride to conscious dogs for 60 min, whereas Pinilla et al.
(21) infused ~170
µmol · kg1 · min1
for 45 min in anesthetized dogs without measuring any change in mean
arterial blood pressure. Recently, Krier and Romero (16) increased mean
arterial blood pressure by 14 mmHg in anesthetized dogs with a load of
130 µmol · kg1 · min1
sodium for 60 min. There is no obvious explanation for the difference between these results; however, it might well be due to differences between the experimental conditions, particularly with regard to sodium
intake and volume status. Nevertheless, our data clearly demonstrate
that infusion of NaCl at rates from 30 µmol · kg1 · min1
may cause immediate blood pressure increases and, in the case of
isotonic loading, also tachycardia.
During and after the infusion period in IsoLoad-20 and HyperLoad-20
series, we observed a natriuretic response without any change in mean
arterial blood pressure. In the latter experiment, the natriuresis
occurred without increases in GFR, possibly because the effects of the
sodium loading were counterbalanced by the decrease in the activity of
the renin-angiotensin system. Other natriuretic factors must,
therefore, be responsible for this natriuresis. An obvious candidate is
ANG II, because plasma levels were inversely correlated with renal
sodium excretion. Figure 3
shows the relationship between mean arterial blood pressure, plasma ANG
II, and renal sodium excretion, with three points from each experiment:
preinfusion, end-infusion, and recovery values. Sodium excretion was
increased only when the plasma levels of ANG II were <10 pg/ml, and
this relationship does not appear to be affected by mean arterial blood pressure changes in the range of 95-125 mmHg. These results
support a number of previous conclusions from both animal and human
investigations (2, 4, 21, 23) that the decrease in plasma levels of ANG
II is a major factor determining sodium excretion during salt loading.
The present study was not designed to evaluate in detail the immediate
effects of a decrease in plasma ANG II on renal sodium handling;
however, the intrarenal effects of ANG II have been studied intensively
in micropuncture experiments. The overall effect of ANG II on proximal
tubular function in vivo is still unclear, but recently it was reported
that ANG II may directly stimulate sodium reabsorption in the distal
tubule of the rat (26). This may explain at least part of the
natriuretic effect of a decrease in plasma ANG II under conditions of
constant arterial blood pressure and GFR. Another possible intrarenal
mechanism is that the decrease in ANG II allows intrarenal hydrostatic
pressure to rise, thereby inhibiting tubular sodium reabsorption (6).
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The explanation for the fall in the activity of the renin-angiotensin system in our experiments is not straightforward, at least not when it occurs without changes in GFR or blood pressure. Plasma ANG II is generated by renin and converting enzyme. Renin secretion is regulated by 1) changes in renal perfusion pressure (14), 2) changes in sodium chloride concentration at the macula densa (24), and 3) changes in renal nerve activity (19). During HyperLoad-20 and IsoLoad-20 experiments, an increase in renal perfusion pressure cannot directly explain the decrease in renin activity, because mean arterial blood pressure did not change. However, regulation of renin secretion by changes in renal perfusion pressure is a complex relationship involving transmural pressure, tangential wall tension, and the arteriolar diameter at the level of the renin-secreting juxtaglomerular cells. Thus it is very difficult to completely dismiss the intrarenal vascular baroreceptor mechanism in the suppression of renin secretion in this study. Increases in sodium delivery to macula densa may have occurred both in HyperLoad-20 and IsoLoad-20 series and elicited decreases in renin secretion and ANG II production. In both series, the filtered load of Na+ was increased: in HyperLoad-20 experiments, plasma sodium increased by 1% and GFR was unchanged; in the IsoLoad-20 series, GFR increased by ~8%, whereas plasma sodium was unchanged. If the macula densa-mediated mechanism was responsible in the former case, then it must be very sensitive and capable of reacting to a 1% increase in filtered load. However, different and very specific experimental approaches are required to evaluate possible relations between filtered load, macula densa electrolyte concentrations, and renin secretion operating at such small deviations.
Changes in renal sympathetic nerve activity may also have been involved in the natriuresis seen during the present experiments. A decrease in renal sympathetic nerve activity is a contributory factor to the natriuresis observed after volume expansion (for review, see Ref. 9) also in conscious dogs (18). Changes in renal sympathetic nerve activity may affect sodium excretion either via changes in renin secretion or by directly affecting tubular transport. The latter was clearly demonstrated in conscious dogs by Persson et al. (20). In our study, sympathetic nerve activity is assumed to be low, because control heart rates were ~55 beats/min. Therefore, withdrawal of renal sympathetic nerve activity under the present circumstances most likely was a mechanism left with only a narrow range of operation. However, we cannot rule out the possibility that a decrease in renal sympathetic nerve activity, small as it might have been, nevertheless played a significant role in the natriuresis during salt loading in this study.
Other factors may have been involved but appear even more unlikely.
Changes in atrial natriuretic peptide (ANP) may have affected sodium
excretion during nonhypertensive salt loading. Plasma ANP was not
measured in the present experiments, because in a previous study (4) it
was found that plasma ANP was not elevated during hypertonic infusion
and made only a small (14%) increase during isotonic infusion of 60 µmol · kg1 · min1,
i.e., 2-10 times the stimulus intensity used in the present work.
A primary role of ANP thus seems highly improbable.
Colloid osmotic pressure has been found to play a substantial role in
renal excretion of salt after volume expansion (8). In the present
study, reductions in colloid osmotic pressure are likely to have
occurred in all infusion series, because plasma protein concentration
changed and it could be argued that this may have contributed to the
natriuretic response to salt loading. However, in our experiments it
seems to be secondary to ANG II, because some 90% of the much larger
natriuretic response to 60 µmol · kg1 · min1
can be blocked by normotensive ANG II clamping (4). Therefore, if
colloid osmotic pressure changes did contribute to the present natriuresis, the effect was probably minor.
Sodium status is normally sensed by volume/baroreceptors (17). However, there are data supporting the notion that osmoreceptors, possibly of central location, also may play a role in the afferent pathway of sodium homeostasis (2, 11-13). In the present study, we found that renal sodium excretion tended to increase to higher levels in HyperLoad-20 and -30 series compared with the corresponding isotonic series, especially during the recovery period, although it did not reach statistical significance. Considering the fact that the degree of extracellular volume expansion elicited by hypertonic saline is smaller than the expansion generated by the same amount of sodium as an isotonic solution, these results indicate that osmoreceptors may play a role in mediating the natriuretic response to a hypertonic sodium load, but further investigation is necessary to illustrate the importance and the effector mechanisms in osmomediated natriuresis.
Plasma osmolality is the major regulator of vasopressin secretion (for
review, see Ref. 3). By intracarotid infusions of sodium chloride
solutions of different tonicity in conscious dogs, Wade et al. (25)
showed that after a threshold, plasma vasopressin increased with
increasing jugular plasma osmolality in a linear relationship. Our
results in this and a previous study (4) support this linear
relationship. The threshold phenomenon for vasopressin secretion was
not addressed by the present experiments, because observations were not
made below plasma osmolality levels of 304 mosmol/kg. The results
illustrate that, above a possible threshold, vasopressin secretion is
extremely sensitive to changes in plasma osmolality. First, it was
found in the HyperLoad-6 series that a 33% increase in plasma
vasopressin occurred while plasma osmolality only tended to increase by
~1 mosmol/kg. The calculated increase in body fluid osmolality
generated by the administration of the 6 µmol · kg1 · min1
load is 1.5 mosmol/kg. Consequently, vasopressin secretion responds to
plasma osmolality changes, which are undetectable by conventional freezing-point osmometry, which, with plasma samples, operates with
coefficients of variation of 0.25-0.40%. Second, the results indicate that the slope of the relationship is ~0.5, i.e., that, for
each milliosmole, plasma osmolality increases plasma vasopressin by 0.5 pg/ml. This appears to be a very steep slope (see Ref. 25). It is possible that the present protocol, which included infusions
of strongly hypertonic saline solutions at very low rates, is more
appropriate for detection of the parameters of the osmoregulatory
control system than previous procedures.
Perspectives
The present study demonstrates that mean arterial blood pressure is very sensitive to slow sodium loading in conscious dogs. This sensitivity appears to be different from that of humans, because sodium chloride may be infused at considerably higher rates in humans without any measured change in mean arterial blood pressure. A comparative investigation of the sensitivity of blood pressure regulation to the rate of infusion of NaCl appears warranted, because species difference (dog to human), if present to any sizable extent, is a necessary prerequisite for appropriate interpretation of quantitative results. The study shows that, even in dogs, natriuresis after a physiological sodium load may easily occur without changes in mean arterial blood pressure and GFR rate and that this natriuresis is inversely associated with plasma levels of ANG II. Therefore, withdrawal of ANG II may be an important component of any volume expansion natriuresis. Acute and chronic nonhypertensive sodium loading may provide detailed quantitative knowledge of the regulatory mechanisms in sodium and water homeostasis, particularly the main sensory mechanism behind and the specific actions of ANG II withdrawal capable of regulating renal sodium excretion by at least one order of magnitude without changes in filtration rate. Such information is crucially important to the understanding of normal body fluid regulation and of different pathophysiological conditions in sodium and water handling, i.e., arterial hypertension and congestive heart failure.| |
ACKNOWLEDGEMENTS |
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The expert technical assistance of Sigurd K. Hansen in the dog laboratory and Birthe Lynderup Christensen, Trine Eidsvold, Inge H. Pedersen, and Barbara Sørensen with the analyses is gratefully appreciated. Aprotinine was kindly provided by Novo Nordisk. Drs. Niels-Henrik Holstein-Rathlou and Paul Peter Leyssac provided valuable insight with regard to the interpretation of the results.
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FOOTNOTES |
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The work was supported by grants from The Danish Medical Research Council, the Novo Nordisk Foundation, and the Velux Foundation.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. Bie, Dept. of Physiology and Pharmacology, University of Odense, 21 Winsløwparken, DK-5000 Odense, Denmark (E-mail: bie{at}imbmed.sdu.dk).
Received 15 March 1999; accepted in final form 26 July 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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, t = 25 min; 
,
t = 115 and 145 min. C and D: urine flow
(ml/min) and free water clearance (ml/min), respectively. 
significantly
different from control series (P < 0.05).
