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J Am Soc Nephrol 11:1293-1302, 2000
© 2000 American Society of Nephrology

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Nitric Oxide Synthesis Inhibition Does Not Impair Water Immersion-Induced Renal Vasodilation in Humans

LIOE-TING DIJKHORST-OEI, PETER BOER, TON J. RABELINK and HEIN A. KOOMANS

Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.

Correspondence to Dr. Hein A. Koomans, Department of Nephrology and Hypertension, University Hospital Utrecht, Room F03.226, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Phone : +31 30 2507329 ; Fax : +31 30 2543492 ; E-mail : H.A.Koomans{at}DIGD.AZU.NL


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Abstract. Nitric oxide (NO) is tonically released in the kidney to maintain renal perfusion and adequate sodium and water clearance. Little is known about the role of NO in the renal adaptation to an acute volume challenge. This is important for our understanding of pathophysiologic conditions associated with impaired NO activity. This study examined the effects of NO synthesis inhibition on neurohumoral, renal hemodynamic, and excretory responses to head-out immersion (HOI). Seven healthy men underwent four 7-h clearance studies. One study served as a time control study (placebo infusion), and in one study NG-monomethyl-L-arginine (L-NMMA ; 3 mg/kg priming dose + 3 mg/kg per h) was infused during hours 2 to 5. In a third and fourth clearance study, HOI was applied from hours 3 to 5, during infusion of either placebo or L-NMMA. To assess the degree of NO synthesis inhibition, the effect of L-NMMA on [15N]-arginine-to-[15N]-citrulline conversion rate was studied in four others. HOI decreased mean arterial pressure (MAP) from 87 ± 3 to 76 ± 2 mmHg and renal vascular resistance (RVR) from 82 ± 6 to 70 ± 7 mmHg · min/L, and increased sodium excretion (UNaV) from 110 ± 27 to 195 ± 29 µmol/min and flow (UV) from 14.4 ± 1.4 to 15.8 ± 1.4 ml/min. L-NMMA caused profound and sustained increases in MAP and RVR and decreases in UNaV and UV. HOI superimposed on L-NMMA infusion decreased the elevated MAP from 93 ± 4 to 83 ± 2 mmHg and RVR from 111 ± 9 to 95 ± 7 mmHg · min/L, and increased UNaV from 41 ± 8 to 95 ± 15 µmol/min and UV from 10.0 ± 1.1 to 12.7 ± 1.4 ml/min. The relative changes were not significantly different from the effects of HOI without L-NMMA infusion. HOI decreased plasma renin activity and aldosterone and increased plasma atrial natriuretic peptide and urinary cGMP. L-NMMA decreased urinary cGMP, but did not affect the plasma hormones or the changes induced by HOI. L-NMMA decreased the [15N]-arginine-to-[15N]-citrulline conversion rate to one-third of baseline. The results indicate that in a state of NO deficiency in humans, the kidney can still respond to an acute volume challenge with vasorelaxation, diuresis, and natriuresis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Head-out immersion (HOI) is a model of acute central blood volume expansion. The renal response to this maneuver consists of renal vasorelaxation and diuresis and natriuresis (1). Thus, HOI can be used to study the factors that play a role in acute modulation of renal hemodynamics and excretory function. Among these are suppression of the renin-angiotensin system and sympathetic tone, and stimulation of atrial natriuretic peptide (ANP) and renal vasodilatory prostaglandins (1).

Whether intact nitric oxide (NO) availability is essential for a normal renal response to HOI has not been investigated. Blockade of NO synthesis in animals (2) and humans (3,4) induces strong renal vasoconstriction, accompanied by sodium and water retention, which underscores the importance of NO in keeping the kidney tonically in a vasodilated state and permitting adequate sodium and water excretion. Stimulation of NO synthesis, for instance by bradykinin, induces marked vasodilation natriuresis and diuresis (5). That NO plays a role in the physiologic response to HOI is therefore conceivable. However, because many other mediators are involved, the role of NO could be purely a modulating one rather than a mediating one.

Apart from being relevant for normal physiology, this issue is relevant for our understanding of essential hypertension. This condition has been associated with impaired availability of NO (6,7,8). Patients with essential hypertension display an impaired renal vasodilatory response to L-arginine infusion (9). This is particularly the case in patients with salt-sensitive hypertension (10), a condition that may be specifically related to impaired NO activity (11,12). Nonetheless, the renal vasodilatory and natriuretic response to an acute volume challenge is normal or paradoxically increased (13,16).

We therefore studied the acute renal responses to HOI in healthy humans with and without NO synthesis inhibition induced by infusion of NG-monomethyl-L-arginine (L-NMMA). This NO synthesis inhibitor was infused for several hours to induce steady-state conditions. The magnitude of NO synthesis inhibition was assessed from the effect of L-NMMA on the [15N]-arginine-to-[15N]-citrulline conversion rate. Details of this technique were published recently (17).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Water Immersion Experiments
Studies were carried out in seven healthy men (age range, 20 to 25 yr). Their health status was assessed by medical history, physical examination, and routine laboratory investigation. All participants gave written informed consent after extensive explanation of the protocol. The study protocol was approved by the University Hospital Ethical Committee for Studies in Humans.

Each subject underwent two clearance experiments while remaining seated in air (air temperature 26.0 ± 1.0°C), and two clearance experiments while undergoing HOI for 3 h. In either two conditions, one experiment was performed during L-NMMA infusion to inhibit NO synthesis and the other during placebo (vehicle) infusion. Infusion of either L-NMMA or placebo was started after completion of the 1-h baseline collections. L-NMMA (Institut für Pharmazie, Universität Leipzig, Germany) was dissolved in normal saline (5 mg/ml) and infused as a priming dose of 3 mg/kg body wt, followed by maintenance infusion of 3 mg/kg per h during 4 h, from hours 2 to 5. This scheme was chosen to achieve a period of steady state, such as is desired for studies using clearance techniques. The average volume infused was 220 ml over 4 h. In the two HOI studies, after 1 h of infusion subjects were immersed in thermoneutral water (35.5 ± 0.5°C) up to the sternoclavicular notch. Immersion was thus applied from hour 3 to hour 5, with only brief interruptions for urine collection, and ended at the same time as the infusion period. After cessation of the infusion period, recovery was observed for 2 more hours.

The 7-h clearance studies were carried out on separate days at least 3 d apart. The order of the studies was randomized. The studies were performed after 5 d of a diet containing 200 mmol sodium. Adherence to the diet was monitored by 24-h urine collections on the day before each clearance experiment.

On the eve of each clearance study, 400 mg of lithium carbonate was ingested at 10 p.m. The experiments were started by subjects receiving an oral water load of 25 ml/kg between 7:30 a.m. and 8.30 a.m. Additional water-matching urine output was supplied throughout the clearance study. An antecubital vein was catheterized bilaterally for separate blood sampling and infusions. At 9 a.m., a priming dose of a solution containing 10% inulin, to measure GFR, and 2.5% para-aminohippuric acid, to measure effective renal plasma flow (ERPF), was given, followed by continuous infusion of this solution throughout the remainder of the study. After at least 1 h equilibration, and when urine osmolality had reached a stable value of 70 mosmol/kg or less, three 20-min baseline urine collections were obtained by spontaneous voiding. Blood specimens were drawn at the midpoint of each collection period. Urine collection and midpoint blood sampling were continued at 30-min intervals throughout the study. BP was recorded at 5-min intervals using an automated oscillometer device (Omega 1400 ; Invivo Research Laboratory, Tulsa, OK), and care was taken that the measurement arm and pressure cuff were kept at the same level relative to the heart throughout the study.

Blood and urine samples were analyzed for sodium and potassium (flame photometry), chloride (Technicon RA-1000 autoanalyzer), lithium (Perkin-Elmer 3030 Atomic Absorption Spectrophotometer ; Norwalk, CT), osmolality (Advanced Digimatic Osmometer), and inulin and para-aminohippurate (18,19). Additional blood samples for determination of vasoactive hormones were drawn at t = 30, t = 105, t = 285, and t = 345. RIA determination of plasma renin activity (PRA), aldosterone, and ANP was performed as described previously (20). Urine samples collected at baseline and at hours 2, 5, and 7 were analyzed for cGMP using an RIA kit with tritium-labeled cGMP (Amersham International, Buckinghamshire, United Kingdom).

Clearances were calculated according to standard formula. Mean arterial pressure (MAP) was calculated as the sum of one-third of systolic pressure and two-thirds of diastolic pressure. Renal blood flow was calculated by dividing ERPF by (1-packed cell volume). MAP was divided by renal blood flow to estimate renal vascular resistance. The changes induced by HOI were corrected for the changes found during the control studies. For this purpose, the ratios of the individual values during the HOI study and the corresponding control study were calculated for each urine collection period.

[15N]-Arginine-to-[15N]-Citrulline Conversion Rate Experiments
As a measure of whole-body NO synthesis before and during the NO synthase (NOS) blockade, the [15N]-arginine-to-[15N]-citrulline conversion rate was determined in four healthy volunteers (3 male, 1 female, age range 22 to 28 yr) at baseline and until 2 h after the start of L-NMMA infusion, using the same protocol as in the clearance studies (3 mg/kg priming dose, followed by 3 mg/kg per h). The protocol was approved by the University Hospital Ethical Committee for Studies in Humans, and subjects provided written informed consent after explanation of the protocol.

Two hours before L-NMMA infusion was started, two blood samples were obtained for determination of (natural) background isotope ratios. Then subjects received a priming dose of 12 µmol L-[guanidino-15N2O]-arginine (purity >98% atom percent excess (APE) ; Mass Trace, Woburn, MA) per kilogram body weight in 2 min, followed by a constant infusion of 11.2 µmol/kg per h. After 1 h, three blood samples for measurement of steady-state baseline enrichments were collected at 30-min intervals. Subsequently, L-NMMA administration was started and blood sampling at 30-min intervals was continued for another 2 h.

Arginine and citrulline 15N enrichment in plasma was determined by electrospray ionization mass spectrography with a VG Platform single quadrupole instrument after separation using a Pharmacia Smart System, equipped with a 4 x 250 mm Sephasil C18 column, a fraction collector, and an ultraviolet detector (Pharmacia Biotech, Uppsala, Sweden). The wavelength was set at 214 nm. Additional details of the technique have been published recently (17).

Enrichments were expressed as APE (21) :

(1)
where rsa is the isotope ratio of an enriched sample, and rbg is the (natural) background ratio of a preinfusion sample. Plasma arginine fluxes were calculated from the enrichment of plasma arginine during steady-state infusion, using the single pool model for flux as described by Clarke and Bier (22) :

(2)
where Qarg is the arginine flux (µmol/kg per h), Iarg is the infusion rate of labeled arginine (µmol/kg per h), APEinf is the enrichment of infused arginine, and APEarg is the enrichment of plasma arginine during steady-state infusion. Arginine-to-citrulline conversion rates were calculated according to Thompson et al. (23) :

(3)
where Qarg->cit is the arginine-to-citrulline conversion rate (mol/kg per h), Qcit is the citrulline flux (a value of 9.5 mol/kg per h as reported by Castillo et al. [(24)] was used), APEcit is the enrichment of plasma citrulline during steady-state infusion, and the term [Qarg/ (Qarg + Iarg)] is a correction for the contribution of the infused arginine to Qarg->cit.

Statistical Analyses
The results are expressed as means ± SEM. For statistical analyses, data were subjected to ANOVA for repeated measures, followed by post hoc multiple comparisons with the Student-Newman-Keuls test if variance ratios reached statistical significance. Plasma aldosterone levels were analyzed after logarithmic transformation. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clearance Experiments
Basal Data and Placebo Infusion.
There were no significant differences in the baseline values between the study days. Both hemodynamic and renal function parameters indicated that the subjects were in a steady state before the start of the infusions (Figures 1 and 2). The placebo control study showed a significant decrease in plasma aldosterone between baseline and the end (hour 7) of the experiment. This was associated with a fall in potassium excretion (Table 1) and in plasma potassium from 4.2 ± 0.3 (baseline) to 3.5 ± 0.3 mmol/L (hour 7 ; P < 0.05).



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  		Figure 1. Renal hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA) infusion (A) and heat-out immersion (HOI) (B) in seven healthy men. Values are means ± SEM. {circ}, placebo control study ; •, L-NMMA control study ; {triangleup}, placebo infusion with HOI ; {triangleup}, L-NMMA infusion with HOI. MAP, mean arterial pressure ; RBF, renal blood flow ; RVR, renal vascular resistance.

 


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  		Figure 2. Effects of L-NMMA infusion (A) and HOI (B) on renal function in seven healthy men. Values are means ± SEM. {circ}, placebo control study ; •, L-NMMA control study ; {triangleup}, placebo infusion with HOI ; {triangleup}, L-NMMA infusion with HOI. UNaV, urine sodium excretion ; UVMAX, maximum urine flow.

 

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  		Table 1. Effects of NOS inhibition on urine electrolyte excretions and minimal osmolality a
 

Effects of L-NMMA Infusion.
L-NMMA infusion caused a profound increase in MAP and renal vascular resistance and a decrease in renal blood flow (Figure 1A, Table 2) and GFR (Figure 2A). L-NMMA also caused a significant fall in sodium and water excretion (Figure 2A). All of these changes were obtained immediately after the start of L-NMMA infusion, and lasted throughout the infusion period. Chloride excretion decreased as well, whereas potassium excretion remained unchanged (Table 1). The sodium retention was associated with an increased tubular sodium reabsorption, as indicated by a fall in fractional sodium excretion. Fractional lithium excretion and minimal urine sodium concentration decreased as well, whereas minimal urine osmolality increased. The decrease in plasma aldosterone, urine potassium excretion, and plasma potassium (from 4.3 ± 0.4 mmol/L at baseline to 3.5 ± 0.3 mmol/L in hour 7, P < 0.05) was similar to that in the placebo control experiment. L-NMMA also had no effect on PRA or ANP, but decreased urinary cGMP (Table 3).


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  		Table 2. Effects of HOI during L-NMMA or placebo infusion on blood pressure and RVR a
 

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  		Table 3. Effects of NOS inhibition on neurohumoral changes induced by HOI a e
 

Effects of HOI during Placebo or L-NMMA Infusion.
HOI caused an immediate and sustained decrease in MAP of 12 ± 2% (P < 0.01) (Figure 1B, Table 2). Renal blood flow did not change significantly. Renal vascular resistance, averaged for the 3-h immersion period, showed a mean decrease of 14 ± 5% (P < 0.05). In the experiments in which HOI was preceded by L-NMMA infusion, we first observed that the L-NMMA infusion per se caused very similar changes in renal hemodynamic and excretory parameters as in the previous experiments. Thus, these effects of L-NMMA appeared very reproducible. When HOI was superimposed over L-NMMA infusion, MAP fell by 11 ± 3% (P < 0.01) to pre-L-NMMA levels, but renal blood flow remained significantly reduced, so that renal vascular resistance decreased by 17 ± 4% (P < 0.05). These percent changes were similar as found when HOI was applied during placebo infusion (Figure 1B, Table 2). The recovery period after HOI showed a transient renal vasoconstriction (P < 0.01 both in L-NMMA and placebo-infusion studies) (Figure 1B).

HOI had no consistent effect on GFR, but caused a significant increase in sodium and water excretion (Figure 2B, Table 4). With correction for the changes during placebo infusion alone, HOI increased sodium excretion by 146 ± 34% and maximal urine flow by 21 ± 6% after 3 h (both P < 0.01). When superimposed over L-NMMA infusion, HOI increased sodium excretion by 199 ± 40% and maximal urine flow by 45 ± 14%. These percent changes were not significantly different from those during HOI alone. Chloride excretion followed the excretory pattern of sodium (Table 4). HOI caused a slight increase in potassium excretion, but not when applied during L-NMMA. The natriuretic response to HOI was associated with an increase in fractional excretion of sodium and lithium, and in minimal urine sodium concentration. These changes were also found when HOI was superimposed on L-NMMA infusion. In fact, it appeared that HOI reversed the changes in renal water and electrolyte handling induced previously by L-NMMA.


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  		Table 4. Effects of HOI during L-NMMA or placebo infusion on urine electrolyte excretions and minimal osmolality a
 

HOI induced consistent suppression of PRA and plasma aldosterone, and stimulation of plasma ANP and urinary cGMP excretion (Table 3). Similar changes were found when HOI was applied during L-NMMA infusion. Notably, L-NMMA infusion had decreased urine cGMP, but did not prevent its rise during HOI.

Effect of L-NMMA on [15N]-Arginine-to-[15N]-Citrulline Conversion Rate
Plateau levels of basal [15N]-citrulline enrichment and enrichment in the NOS-inhibited state were reached within 1 h after the start of [15]-arginine and L-NMMA infusions, respectively (Figure 3). Average absolute [15N]-arginine-to-[15N]-citrulline conversion rate was 0.30 ± 0.07 µmol/kg per h at baseline and fell to 0.10 ± 0.03 µmol/kg per h in the second hour of L-NMMA infusion.



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  		Figure 3. Whole-body nitric oxide (NO) synthesis before and during 2-h L-NMMA infusion in four healthy subjects, assessed by measurement of conversion of infused [15N]-arginine to [15N]-citrulline.

 


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Under basal circumstances, HOI decreased MAP and renal vascular resistance, which resulted in unchanged renal blood flow. HOI did not significantly affect GFR. Sodium excretion, lithium excretion, and maximum urine flow increased over the 3-h immersion period. These observations confirm earlier reports on the renal effects of HOI and have been discussed in detail previously (1, 25). After immersion, all changes were reversed. In previous studies, others (26, 27) and ourselves (25) found that HOI caused some increase in renal blood flow, but an unchanged renal blood flow as found presently has been reported also (28). Perhaps the renal vasodilation is limited by its autoregulatory tendency to maintain perfusion.

L-NMMA infusion caused profound renal vasoconstriction so that renal blood flow was reduced by about one-third. There was a relatively modest increase in MAP. We previously reported that total peripheral resistance increases less than renal vascular resistance upon L-NMMA infusion (4), indicating that the kidney is relatively sensitive to NOS inhibition (29, 30). NOS inhibition also induced substantial sodium retention, while GFR decreased relatively little. The decreased lithium clearance suggests increased proximal tubular sodium reabsorption (31), and the decreased urine sodium concentration, despite increased minimal urine osmolality, suggests increased sodium reabsorption in the segment (32). L-NMMA did not change PRA and aldosterone. It should be mentioned that the effect of NOS inhibition on renin release is complex and controversial, and dependent on multiple factors such as duration and specificity of NOS inhibition, and the study model (33). Such a discussion is beyond the scope of our study, but it should be noted that the unchanged PRA and aldosterone after acute NOS inhibition confirms earlier observations in humans by others (3, 34) and ourselves (32). Aldosterone levels decreased over time during both placebo and L-NMMA control study. We have not investigated the cause of this phenomenon, but it may be explained by the slight but significant concomitant decrease in serum potassium concentration that we observed, possibly as an effect of maximal diuresis over a prolonged period of time.

This is the first study in humans to question whether an intact NO system is needed for the renal hemodynamic and natriuretic changes that follow a volume challenge. We found that during a state of NOS inhibition, the kidney still shows vasorelaxation, natriuresis, and diuresis in response to HOI. In fact, relative to the basal state, the HOI-induced changes were similar to those found during placebo infusion. HOI-induced changes in intrarenal sodium handling also appeared unaltered. It has been reported that NOS inhibition impairs the natriuretic and diuretic response to acute volume expansion in dogs (35) and monkeys (36). Nonetheless, there is no principle difference with the present data in humans. In the former study in dogs (35), NOS inhibition decreased both basal and volume expansion-induced natriuresis, but the relative increase after volume expansion was unchanged. The volume chanllenge did not affect renal plasma flow in these experiments. In the study in monkeys (36), NOS inhibition also decreased basal excretion rate, which in fact was still falling when expansion was started. The relative increase in sodium excretion after volume expansion was somewhat decreased, but the absence of a steady state makes that finding difficult to interpret. NO synthesis inhibition decreased plasma flow by about 30%, but did not prevent its increase induced by the volume challenge (36). This accords well with the present findings in humans. Therefore, it is unlikely that changes in NO activity participate in the mediation of the renal responses to a volume challenge. However, basal NO activity modulates the level at which changes take place, as is apparent from the shifts in renal vascular resistance and sodium excretion curves induced by L-NMMA (Figures 1 and 2).

The background for the idea that NO release might participate in the mediation of the renal responses to HOI is that the primary events are an increase in central blood volume and cardiac output (26, 37, 38). Conceivably, the subsequent peripheral and renal vasodilation is at least partly flow-dependent, which would involve release of NO. Because L-NMMA did not impair vasodilation, we have to assume that this change is not flow-dependent. Apparently, other neurohumoral changes known to follow HOI are able to cause vasodilation also during suppressed NO synthesis. In this respect, it is important that L-NMMA did not prevent the HOI-induced suppression of PRA and stimulation of plasma ANP and urinary cGMP. Regarding the latter, it is important to realize that it is second messenger for both ANP (39) and NO (40). Thus, the presently observed suppression by L-NMMA of basal renal cGMP excretion is in accordance with decreased NO activity, whereas the unimpaired increase of urinary cGMP induced by HOI reflects the stimulation of ANP.

It could be argued that the NOS blockade applied in the present study was not strong enough to reveal a possible role of NO in the flow-mediated changes in the kidney. Indeed, we have not tested higher doses of L-NMMA, and therefore it cannot be concluded that NOS was completely blocked or that NO is not at all involved in the renal effects of HOI. However, because the [15N]-arginine-to-[15N]-citrulline conversion rate decreased by two-thirds upon L-NMMA infusion, it seems likely that we achieved substantial inhibition of whole-body NO activity. In addition, the profound L-NMMA-induced decrease in renal blood flow is in the range of the 25 to 40% reduction observed in animals upon maximum systemic NOS blockade as assessed by pressor effects (2, 29), indicative of near-maximum blockade of renal NOS in our protocol.

Apart from being relevant for normal physiology, our data are important for understanding the hypertensive conditions that are associated with decreased NO availability. Decreased NO-dependent vasodilation has been described in patients with nephrotic syndrome (41), renal insufficiency (42), preeclampsia (43, 44), and essential hypertension (6,7,8). Impaired NO-dependent renal vasodilation has been described in particular in those patients who are salt-sensitive (10). In animal models of spontaneous hypertension, salt sensitivity of the BP is associated with decreased NO activity (11, 12). However, even though the NO-dependent vasodilation is abnormal, the renal vasodilatory response to a volume challenge is not necessarily decreased. Water immersion causes a normal renal vasodilatory response in patients with nephrotic syndrome (45). In patients with essential hypertension, the vasodilatory response to a volume challenge is normal or paradoxically increased (13, 15, 16). This agrees with the present observation that experimental NO synthesis inhibition did not impair the renal vasodilatory response to water immersion. By this reasoning, it is relevant that the degree of NO synthesis inhibition obtained experimentally was at least as strong as present spontaneously in disease. We found recently that whole-body NO production assessed from the [15N]-arginine-to-[15N]-citrulline conversion rate was reduced to about one-third of normal in patients with chronic renal failure (46). Regarding essential hypertension, comparable isotope conversion studies measuring urinary [15N]nitrate excretion demonstrated a reduction in NO generation in patients of 35 to 40% (47). The L-NMMA infusion used in the present study suppressed [15N]-arginine-to-[15N]-citrulline conversion rate to about one-third of baseline, and we may assume that the inhibition of NO synthesis achieved was at least as strong as in the aforementioned disease states.

In conclusion, strongly reduced NO availability in humans does not impair the acute changes in renal hemodynamics and sodium excretion in response to water immersion. NO substantially influences the basal conditions, and thus the level at which the renal response occurs, but does not seem to be an essential mediator. The normal responses can probably be attributed to adequate mobilization of other systems, including suppression of the renin-angiotensin system and increased release of ANP. The clinical relevance of these observations pertains to humans with disease conditions associated with impaired NO activity. It follows that their reduced NO availability will by itself not attenuate the renal response to an acute volume challenge such as HOI.


   Acknowledgments
 
This study was supported by a grant from the Dutch Kidney Foundation.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication September 17, 1998. Accepted for publication October 9, 1999.




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M. Schou, A. Gabrielsen, N. E. Bruun, P. Skott, B. Pump, H. Dige-Petersen, E. Frandsen, P. Bie, J. Warberg, N. J. Christensen, et al.
Angiotensin II attenuates the natriuresis of water immersion in humans
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R187 - R196.
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