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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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.
The
importance of arterial blood pressure (BP) and ANG II for the renal
natriuretic response (NaEx) to volume expansion (3.5% body wt) was
investigated during converting enzyme blockade (enalaprilate, 2 mg/kg).
In separate experiments, BP was clamped either 30 mmHg above or a few
millimeters mercury below baseline by servo-controlled infusion of ANG
II or sodium nitroprusside, respectively, so that volume expansion did
not change BP. Enalapril decreased BP by 8 mmHg. Without
clamping, volume expansion returned BP to that of preenalapril control
and increased NaEx 10-fold (40 ± 10 to 377 ± 69 µmol/min). During
high pressure clamping (133 ± 2 mmHg), peak NaEx after volume
expansion was 6% of control experiments. During low pressure clamping,
NaEx was 68% of control experiments (45 ± 15 to 256 ± 64 µmol/min). The results show that 1) in absence of ANG II,
volume expansion elicited pronounced natriuresis without increases in
BP beyond baseline, 2) in the presence of hypertensive amounts
of ANG II, the volume expansion-induced natriuresis was almost
eliminated, and 3) nitroprusside prevented the increase in BP
but not sodium excretion during volume expansion. ANG II appears to
dominate the control of NaEx; however, when absent, volume expansion
may still induce marked natriuresis even at constant BP, possibly via
nitric oxide-mediated mechanisms.
sodium excretion; pressure natriuresis; angiotensin II; converting enzyme inhibition; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE CONTROL OF RENAL SODIUM excretion is multifactorial, involving physical, neural, and humoral mechanisms. However, the relative contributions of the individual components are still controversial, e.g., the importance of arterial blood pressure versus the role of the renin-angiotensin system is still unclear. We recently demonstrated (2) that infusion of a physiologically relevant sodium load, which produced a profuse natriuresis within hours, was associated with an increase in arterial blood pressure of only a few millimeters mercury. Additionally, if the plasma concentration of ANG II was maintained slightly above normal by intravenous infusion of ANG II, the natriuretic response to acute sodium loading was almost eliminated. Thus it seems that the plasma concentration of ANG II also acutely plays an important role in the control of renal sodium excretion. This notion is supported by the results in humans by Singer et al. (20), who showed that ANG II suppression is a major factor permitting the excretion of an acute sodium load. However, it cannot be excluded that the concomitant increase in arterial blood pressure, small as it may appear, was at least a necessary prerequisite for the natriuresis of sodium loading. The present study was designed to test this hypothesis. Arterial blood pressure was maintained at predetermined levels either above or below that observed during basal conditions by servo-controlled infusion of either ANG II or sodium nitroprusside (SNP), respectively, before, during, and after acute volume expansion.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Experiments were performed in six conscious female Beagle dogs weighing 12.0-15.0 kg. The dogs were kept on a fixed diet of dog food (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. The dogs had free access to tap water. Before the study, all animals underwent two surgical interventions in which displacement of both common carotid arteries into skin loops, a chronic episiotomy, and bilateral oophorosalphingohysterectomy were performed (see Ref. 2 for details). The dogs had no complications after surgery and were trained for several months before experiments. The experimental procedures were approved by the Danish Animal Experiments Inspectorate.Experimental Protocol
The same six dogs were used for all experiments. In each dog, experiments were performed at intervals of at least 1 wk. At midnight before the experiment, an electric valve controlled by a timer interrupted the water supply. Baseline conditions were thus characterized by 9 h of water deprivation. The dog was transferred to the laboratory at 0800. A sterile catheter (Intracath, Becton Dickinson, Sandy, UT) was introduced into the right atrial area via the external jugular vein and used for infusions. Another catheter (Insyte-W, Becton Dickinson) was placed in a common carotid artery, allowing continuous measurements of BP interrupted by periodic sampling of arterial blood. A modified silicone Foley catheter (Norta, Beiersdorf, Hamburg, Germany) was used for catheterization of the bladder. An intravenous bolus of creatinine (8.2 ml
14 mg/kg) was
given 1 h before the start of the experiment followed by a continuous
infusion (7.2 ml/h 0.21
mg · kg
1 · min1)
throughout the experiment. In case of servo control of BP, baseline data were collected for 30 min (t = 
30 to
t = 0 min). In all experiments, an intravenous bolus injection
of the converting enzyme inhibitor enalapril maleate (2 mg/kg, Sigma,
St. Louis, MO) was administered at t = 0. Urine was sampled
every 30 min. After two 30-min control periods, isotonic volume
expansion was initiated and continued for 90 min (t = 60-150 min) at a rate of 60 µmol · kg1 · min1,
corresponding to a rate of 0.39 ml · kg1 · min1.
Two 30-min recovery periods completed the experiment (t = 150-210 min).
The first sample of arterial blood was obtained at t = 5
min for determination of plasma electrolytes, creatinine, and
osmolality, and, afterward, samples were obtained 25 min into each
sampling period. Samples of 1 ml drawn at t = 25, 85, 115, and
175 min were used for creatinine determination, whereas electrolyte,
hormone, and creatinine concentrations were measured from 16-ml samples obtained at t = 55, 145, and 205 min.
Arterial blood pressure was measured continuously by a pressure transducer (Statham P50, Gould) connected to a clinical monitor (Dialogue 2000, Danica Elektronik, Rødovre, Denmark). This provided mean arterial blood pressure from the pressure signal on the basis of a 300-Hz analog-to-digital sampling frequency over a 7-s time window. Heart rate was obtained from the electrocardiogram. The monitor data were sampled every 5 s by computer and subsequently averaged over 30-min periods. In case of servo control of BP, the 5-s values were relayed to an additional computer. With the use of custom-designed software (LabVIEW), this personal computer adjusted the speed of an infusion pump administering either a vasoconstrictor agent (ANG II) or a vasodilator agent (SNP) by simple error-activated, proportional control. The gain was optimized to smoothly maintain elevated or reduced arterial blood pressures, respectively, under the given physical and biological delays. The set points are described below. The responses to volume expansion with and without servo control of BP above or below baseline were investigated in separate experimental series.
Control series. In the control series (E), the only intervention was converting enzyme inhibition by enalaprilate.
Isotonic series. In the isotonic series (EIso), converting enzyme inhibition was followed by isotonic volume expansion.
Isotonic + ANG II series. In the isotonic + ANG II series (EIsoANG II), at the time of converting enzyme inhibition, servo-controlled infusion of ANG II (Sigma) was initiated. ANG II was dissolved in a glucose-urea solution (0.6 µg/ml). The amount infused throughout the experiment (210 min) was on the order of 30-40 ml, corresponding to 18-24 µg ANG II. On the basis of the level of baseline arterial blood pressure before converting enzyme inhibition, the servo-control mechanism (see above) kept arterial blood pressure elevated by ~30 mmHg before, during, and after isotonic volume expansion. During volume expansion, the set point was adjusted a few millimeters mercury downward to ensure that blood pressure did not increase further.
Isotonic + SNP series. In the isotonic + SNP series (EIsoSNP), together with converting enzyme inhibition, a servo-controlled infusion of SNP (Nipride, Hoffmann-La Roche, Basel, Switzerland) was initiated. By servo-controlled infusion (see above), the arterial blood pressure was kept slightly below baseline before, during, and after isotonic volume expansion. The set point was defined as 5 mmHg below the lowest value of arterial blood pressure of the same dog during enalapril blockade (control series). During volume expansion, the set point was adjusted a few millimeters mercury downward to ensure that the blood pressure did not increase because of this procedure.
Analyses
The concentrations of sodium and potassium ions in plasma and urine were measured by flame photometry (IL243 flame photometer, Instrumentation Laboratory, Lexington, MA). Plasma and urine osmolality was determined by freezing-point depression (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 Jaffé's reaction modified from Bonsnes and Taussky (4).Hormones
The analyses of hormone levels in plasma were performed by radioimmunoassay after extraction, as recently described (8).ANG II
To determine ANG II immunoreactivity in plasma, a specific antibody (Ab-5-030682) produced by P. Christensen was used as recently described (2). The detection limit was 1.4 pg/ml, and the mean extraction recovery of unlabeled ANG II added to plasma was 88%. Intra- and interassay coefficients of variation were 5 and 12%, respectively.Aldosterone
Plasma aldosterone was measured using a commercial kit (COAT-A-COUNT, Diagnostic Products, Los Angeles, CA). The detection limit was 12.5 pg/ml, and the intraassay coefficient of variation was <4%.Atrial natriuretic peptide
A specific antibody (AB95069/5) produced in this laboratory was used in a final dilution of 1:27,000 according to the procedure of Schütten et al. (19). The detection limit was 1.5 pg/ml, and the mean extraction recovery of unlabeled atrial natriuretic peptide (ANP) added to plasma was 74%. The intra- and interassay coefficients of variation were 6 and 8%, respectively.Vasopressin
Plasma vasopressin (AVP) was measured using an antibody (AB3096) produced in this laboratory. The assay was performed according to Emmeluth et al. (9) at a final dilution of 1:800,000. Cross reactivity was determined for a number of analogous peptides: [Lys8]-vasopressin, oxytocin, and pressinoic acid, all <0.001%, [deamino-Cys1,D-Arg8]-vasopressin <0.07%, and [Arg8]-vasotocin <0.25%. The detection limit was <0.2 pg/ml, and the mean recovery of unlabeled AVP added to plasma was 66%. Intra- and interassay coefficients of variation were <8%.Statistics
Data are presented as means ± SE. The results were evaluated by one-way ANOVA for repeated measurements within groups. 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
Enalapril reduced mean arterial blood pressure for the duration of the experiment (E series; Fig. 1): blood pressure fell from a mean of 104 ± 2 to a nadir of 96 ± 3 mmHg reached within 90 min after administration. In the volume expansion experiments (EIso series; Fig. 1), the blood pressure decrease was very similar (103 ± 3 to 95 ± 3 mmHg) and subsequent volume expansion was associated with a significant increase in BP to a level (105 ± 3 mmHg) not statistically different from the level before converting enzyme blockade.
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With continuous infusion of ANG II (EIsoANG II), BP increased from 104 ± 2 to values between 129 ± 3 and 133 ± 2 mmHg, fulfilling the
goal of elevating BP by ~30 mmHg. Volume expansion during ANG II
infusion did not increase BP further because of the servo system, which
concomitantly reduced the rate of ANG II infusion. This is reflected by
the decreases measured in plasma ANG II concentrations (Fig. 2).
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When nitroprusside was infused (EIsoSNP series), the aim was to keep BP slightly below that of the control experiments and prevent the increase in BP normally occurring during volume expansion, i.e., the 10-mmHg increase observed in the EIso series. The increase was thus prevented at the expense of an increase in the rate of nitroprusside infusion. The protocol, including the minor adjustments of the set point, was successful in the way that BP during infusion of nitroprusside decreased from a control value of 105 ± 2 mmHg and for the remainder of the experiment varied between 93 ± 1 and 89 ± 2 mmHg with a small, but significant decrease, during volume expansion (Fig. 1).
Under control conditions the heart rate was low and constant (Table
1), compatible with low and stable
sympathetic nerve activity. Administration of enalapril, ANG II, or SNP
did not influence HR despite the, in some cases substantial, changes in BP. In all series involving volume expansion, significant increases in
HR in response to saline infusion were observed (Bainbridge reflex).
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Plasma Electrolytes, Osmolality, and Protein Concentration
As illustrated in Table 1, plasma sodium concentrations varied between 142.8 ± 0.5 and 146.5 ± 0.7 mmol/l and showed no significant alterations, except during EIsoSNP, where an increase of 2.0 mmol/l during volume expansion reached significance. Plasma potassium concentrations remained unchanged in all experiments except for a transient increase during EIsoANG II, reaching significance from control and recovery values. Plasma osmolality varied between 302.5 ± 1.1 and 306.7 ± 1.0 mosmol/kg and remained unchanged during EIsoANG II, whereas a small, but significant, decrease between 1.4 and 2.7 mosmol/kg was observed during E, EIso, and EIsoSNP. Plasma protein decreased significantly in all series.Hormones
As shown in Fig. 2, plasma concentrations of ANG II decreased to values below assay detection limit (1.4 pg/ml) in response to administration of enalapril, indicating adequate inhibition of converting enzyme. The plasma level of ANG II required to elevate BP ~30 mmHg before volume expansion was 113 ± 33 pg/ml. During volume expansion, the servo-controlled infusion pump adjusted the rate of ANG II infusion downward because of the pressor effect of volume expansion per se as observed in the EIso series, and the plasma concentration of ANG II was reduced to 41 ± 14 pg/ml. After termination of the volume expansion, the level was once more increased to 96 ± 37 pg/ml. Thus the hypertensive effect of the volume expansion was largely restricted to the period of infusion. Plasma concentrations of aldosterone were low after administration of enalapril and were unaffected by volume expansion (E and EIso, values between 13 ± 0 and 31 ± 14 pg/ml). Infusion of ANG II was associated with increased levels of aldosterone (values between 106 ± 36 and 166 ± 22 pg/ml). During EIsoSNP, plasma levels of aldosterone were in all cases below assay detection limit (13 pg/ml). Plasma concentrations of ANP and AVP seem to be affected by the administration of enalapril, although we did not collect basal values in the present study. Compared with basal values of the same dogs obtained in earlier experiments (2, 18), plasma ANP was increased on the order of 20 pg/ml, whereas plasma AVP was decreased from values between 0.70 and 1.25 pg/ml to values between 0.34 and 0.54 pg/ml. Plasma concentrations of ANP and AVP both increased during the ANG II infusion. The covariation between plasma concentrations of ANG II and AVP was also present during the EIsoANG II series, where a fall in ANG II infusion rate during concomitant volume expansion was associated with a fall in plasma AVP. During recovery, plasma AVP increases in response to increasing plasma ANG II.Renal Variables
Administration of enalapril per se led to an increased rate of urinary sodium excretion (E series, Fig. 1) compared with dogs that underwent the same experimental protocol except for converting enzyme inhibition (2), and stayed at this elevated level throughout the time control experiments. Additional volume expansion (EIso series, Fig. 1) caused a marked increase in sodium excretion from a baseline of 45 ± 11 µmol/min, reaching a maximum of 377 ± 45 µmol/min in the third infusion period. At the end of the experiment, sodium excretion was still substantially elevated (215 ± 20 µmol/min). During the series where infusion of ANG II was performed to elevate blood pressure by ~30 mmHg (EIsoANG II), baseline values were reduced 10-fold and the natriuresis in response to volume expansion was markedly attenuated (5 ± 2 to 23 ± 7 µmol/min) despite the substantial elevation of BP. Renal sodium handling during continuous infusion of nitroprusside (EIsoSNP) followed the same pattern as during EIso, although peak sodium excretion was somewhat lower (256 ± 64 µmol/min) despite the fact that the possible attribution of BP was abolished. The pattern of changes in urine flow in response to interventions was very similar to that of sodium excretion (Table 2). A marked increase in response to volume expansion was observed throughout the experiments during EIso and EIsoSNP (from 0.5 ± 0.0 to 3.1 ± 0.3 and from 0.4 ± 0.1 to 2.1 ± 0.5 ml/min, respectively). Again, baseline values as well as responses to volume expansion were attenuated during EIsoANG II (from 0.1 ± 0.0 to 0.5 ± 0.1 ml/min). There were no significant alterations during the time control experiments (E series). Basal levels of creatinine clearance (Fig. 3) were decreased by ANG II infusion from values between 42.7 ± 3.4 and 46.3 ± 4.0 ml/min to 33.0 ± 2.3 ml/min. Volume expansion was, in all series involving this procedure, associated with a significant increase in creatinine clearance.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present acute experiments performed during near complete blockade of converting enzyme showed 1) that volume expansion elicited a marked natriuresis without increases in blood pressure beyond preblockade control, 2) that most of this response was preserved under conditions where the blood pressure increase during volume expansion was totally prevented by concomitant administration of nitroprusside, and 3) that clamping of arterial pressure at a level 30% above normal by ANG II infusion reduced both control sodium excretion and peak natriuretic response by nine-tenths. These results indicate that the relationship between blood pressure and sodium excretion is instantaneously changed by physiological increases in plasma ANG II and that such changes dominate the control of sodium excretion in the face of blood pressure increases up to 30%.
The role of changes in arterial blood pressure on renal sodium excretion, i.e., the pressure-natriuresis mechanism, is a well-established concept based on extensive experimental material obtained in conscious dogs mostly through chronic studies (days, weeks) by the group of Guyton and Hall (for review, see Ref. 11). Substantial evidence has been presented that elevations of arterial blood pressure, and with that renal perfusion pressure, may be the direct cause of increases in sodium excretion. The same group, however, also obtained results where marked increases in sodium excretion were observed without measurable changes in blood pressure (12). This phenomenon has been explained as the pressure-natriuresis mechanism working with infinite feedback gain, the so called infinite gain principle (for review, see Ref. 10). Several humoral factors as well as sympathetic nerve activity and the composition of the blood may modulate the pressure-natriuresis relationship (for review, see Ref. 6). Most importantly, an increase in plasma ANG II shifts the pressure-natriuresis curve to the right. It was not unexpected, therefore, that the acute inhibition of converting enzyme in the present study decreased blood pressure and increased sodium excretion markedly, i.e., shifted the pressure-natriuresis curve to the left.
Subsequent infusion of a physiological load of sodium as isotonic saline (EIso series) led to a marked increase in sodium excretion, with only a small increase in blood pressure not exceeding preblockade control. The marked natriuresis cannot be attributed to a decrease in ANG II, because this hormone was already maximally suppressed (below assay detection limit). Compared with dogs that underwent the same experimental protocol except for converting enzyme inhibition (2, 18), the present profuse natriuresis (some 5% of the filtered load of Na+) represents an almost threefold elevation of the effect, which, in the previous study, was considered a very substantial natriuretic response. The natriuretic responses in the previous as well as the present work (see below) were almost completely suppressible by exogenous ANG II. Taken together, these results indicate that the enalapril treatment shifted the pressure-natriuresis curve to the left and increased the slope of the curve, because the same small increase in arterial pressure at a lower level resulted in an exaggerated and excessive increase in sodium excretion. An increase in slope is difficult to reconcile with the general concept that ANG II and blood pressure are the dominant controllers of sodium excretion.
Servo-controlled infusion of SNP successfully inhibited the increase in arterial blood pressure in response to volume expansion (EIsoSNP series). Although arterial blood pressure actually decreased by 3-4 mmHg, the volume expansion resulted in a similar rapid and large natriuresis, although not quite to the extent observed in the EIso series. The natriuresis in this case cannot be explained by either increases in arterial blood pressure or decreases in plasma ANG II. The rate of nitroprusside infusion was increased during volume expansion to prevent any increments in blood pressure. Thus it may be assumed that the NO synthase substrate donation by this drug was responsible for part of the natriuresis (for review, see Ref. 15). Although it has not been shown that increased delivery of NO per se increases renal sodium excretion, several other studies indicate that blockade of the NO production reduces the volume expansion-induced increments in sodium excretion (1, 17, 14). Furthermore, a recent study showed that blockade of NO synthesis has significant diminishing effects on volume-induced natriuresis and impairs the natriuresis in a manner that requires further increases in blood pressure to restore the natriuresis (13). All in all, these previous studies and the present data provide evidence that NO shifts the pressure-natriuresis curve to the left, e.g., increases sodium excretion at constant BP. Alternatively, the volume expansion natriuresis in these present series was controlled primarily by factors other than blood pressure. However, it may appear less appropriate to describe an increase in sodium excretion occurring without increases, or, as in this study, together with a significant decrease in blood pressure, as a pressure-natriuresis phenomenon.
Arterial blood pressure was clamped 30 mmHg above control in the EIsoANG II series by servo-controlled infusion of ANG II. Despite the substantial elevation of systemic pressure, baseline sodium excretion was suppressed by 90%. In addition, volume expansion only resulted in very attenuated natriuretic response. Peak response was only 10% of that observed without simultaneous ANG II infusion (EIso). This strongly indicates that decreased levels of plasma ANG II are the single most dominant factor of acute volume expansion natriuresis. This notion is also supported by the findings of Singer et al. (20), who observed that an acute sodium load in normal humans was not excreted unless plasma levels of ANG II were allowed to decrease (20). Whether the effect of ANG II is mediated by direct actions on the tubules or, if a separate mechanism, by shifting of the pressure-natriuresis curve cannot be determined by the data of the present study. However, it is remarkable that very pronounced natriuretic responses were obtained together with only very small or no increases in blood pressure under conditions where ANG II was suppressed by converting enzyme inhibition or allowed to decrease as a result of volume expansion (2, 18), particularly in light of the present finding that substantial acute hypertension failed to overcome the antinatriuretic actions of ANG II. In other words, the rate of excretion of sodium seems also acutely to be dependent more on changes in ANG II than on changes in arterial blood pressure at least as long as both changes are moderate.
It is generally accepted that an increase in arterial blood pressure and, with that, in renal perfusion pressure is associated with a decrease in sympathetic nerve activity. An increase in renal sympathetic nerve activity per se has been shown to elicit an antinatriuretic effect independent of changes in arterial blood pressure and plasma levels of ANG II (16). Withdrawal of renal sympathetic nerve activity might explain the natriuretic response during EIso where a small, but significant, elevation in blood pressure was observed. However, during constantly elevated blood pressure by infusion of ANG II volume, expansion natriuresis was markedly attenuated, and, during EIsoSNP, sodium excretion in response to volume expansion was markedly increased without increments in blood pressure, which is not immediately explicable by changes in renal sympathetic nerve activity. Thus a significant role of the renal sympathetic nerve activity under the present conditions seems unlikely.
A decrease in oncotic pressure is another possible factor influencing renal sodium handling in the present experimental setup. From a study on conscious dogs, Cowley and Skelton (7) concluded that the rapid diuresis and natriuresis after isotonic volume expansion predominantly is a result of plasma protein dilution. Oncotic pressure was not measured in the present study. Bie and Sandgaard (2) observed a decrease in oncotic pressure of ~19% in response to an identical volume expansion. In the present study, plasma protein was observed to decrease in all series. Interestingly, the lowest values were found in EIsoANG II in accordance with the fact that the largest fraction of the infused saline was retained in this series. Therefore, our results indicate that the changes in sodium excretion in response to volume expansion cannot to any significant extent be explained by hemodilution.
In parallel to the observed hemodilution, glomerular filtration rate (GFR) increased in all series involving volume expansion, including the EIsoANG II series. However, in this series, GFR increased from a lower level, which may explain part of the attenuated sodium excretion. From the present data, it is not possible to determine the intrarenal mechanisms by which plasma ANG II affects GFR. It is notable that NO synthase substrate donation by infusion of SNP did not influence GFR. This is in accordance with the findings of Salazar's group (1, 14, 17), who showed repeatedly that blockade of NO did not induce changes in renal hemodynamics.
The different natriuretic responses described above cannot be attributed to the natriuretic effect of ANP, because the highest plasma concentrations of this hormone were observed in the series with the lowest natriuretic response (EIsoANG II). In the absence of other changes, plasma ANP must be elevated rather substantially to induce an immediate natriuresis (3, 5). The present changes appear very small in this context, and it is, therefore, very unlikely that ANP played any significant role in the natriuretic response measured under the present conditions.
An additional experimental series was performed identical to the EIsoANG II series, except that servo-controlled elevation of arterial blood pressure was terminated at t = 150 min, i.e., at the end of volume expansion. Until that point, all responses were similar in the two series. After termination of ANG II infusion, blood pressure decreased toward control level within minutes while sodium excretion, however, stayed suppressed for the remainder of the experiment (peak excretion 55 ± 15 compared with 25 ± 8 µmol/min with ANG II). This finding is not immediately explicable from the parameters measured in the present experiment. One possible explanation could be the elevation of plasma aldosterone generated by the infusion of ANG II. The measured plasma levels of this hormone decreased after stop of ANG II infusion to levels comparable to control (25 ± 6 pg/ml). However, the antinatriuretic effect of aldosterone can be expected to outlast the fall in plasma concentration by ~0.5-1.5 h. Therefore, within the time frame of the present experiments, aldosterone might still be responsible for the antinatriuresis, despite the fall in the concentration in plasma.
Perspectives
The present data provide substantial evidence that the acute physiological excretion of a sodium load is dependent on withdrawal of plasma ANG II, i.e., only when this variable is decreased may other control systems become dominant in control of sodium homeostasis. Thus, also during acute circumstances, the excreted amounts of sodium are related to decrements in plasma ANG II rather than to changes in other parameters, e.g., increases in arterial blood pressure. Seen in the light of the substantial work by Guyton (10), one might speculate that plasma ANG II is the dominant single factor as long as the changes in arterial blood pressure occur within a narrow range around the normal mean, i.e., that this effect can be overridden when the pressure changes are substantial, i.e., exceeds 30 mmHg. Thus it could be hypothesized that the infinite gain principle reflects the effects of small changes in ANG II concentrations rather than small changes in arterial blood pressure.In the absence of both ANG II and changes in arterial blood pressure, a substantial natriuresis was observed in parallel with volume expansion and NO synthase substrate donation, demonstrating that volume expansion natriuresis may occur almost unimpeded in the absence of increases in arterial blood pressure and hinting that NO may play a role in sodium homeostasis, at least when ANG II and blood pressure, the two major controllers, are inoperative. Further investigation of the interaction between NO generation and other natriuretic stimuli may provide novel data with regard to the physiological regulation of renal sodium excretion.
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ACKNOWLEDGEMENTS |
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The expert technical assistance of Sigurd K. Hansen in the dog laboratory and of Birthe Lynderup Christensen, Trine Eidsvold, Inge H. Pedersen, and Barbara Sørensen with the analyses is gratefully appreciated. Aprotinine was kindly provided by Novo Nordisk.
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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, Depart. of Physiology and Pharmacology, Odense University, 21 Winsløwparken, DK-5000 Odense C, Denmark (E-mail bie{at}imbmed.sdu.dk).
Received 15 March 1999; accepted in final form 26 July 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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, isotonic series
(EIso); 
, EIso + ANG II (EIsoANG II) series; 
, EIso + sodium
nitroprusside series (EIsoSNP). Enalapril 2 mg/kg at t = 0 min
in all series. Volume expansion 60 µmol · kg
