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Am J Physiol Regul Integr Comp Physiol 283: R187-R196, 2002. First published March 22, 2002; doi:10.1152/ajpregu.00536.2001
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Vol. 283, Issue 1, R187-R196, July 2002

Angiotensin II attenuates the natriuresis of water immersion in humans

Morten Schou, Anders Gabrielsen, Niels Eske Bruun, Peter Skøtt, Bettina Pump, Harriet Dige-Petersen, Erik Frandsen, Peter Bie, Jørgen Warberg, Niels Juel Christensen, and Peter Norsk

Department of Aviation Medicine, The Heart Centre, The National University Hospital, DK-2100 Copenhagen; Department of Medical Physiology, University of Copenhagen, DK-2200 Copenhagen; Department of Clinical Physiology and Nuclear Medicine, Glostrup University Hospital, DK-2600 Glostrup; Department of Internal Medicine and Endocrinology, Herlev University Hospital, DK-2730 Herlev; Department of Cardiology, Gentofte University Hospital, DK-2900 Hellerup; and Department of Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The hypothesis was tested that suppression of generation of ANG II is one of the mechanisms of the water immersion (WI)-induced natriuresis in humans. In one protocol, eight healthy young males were subjected to 3 h of 1) WI (WI + placebo), 2) WI combined with ANG II infusion of 0.5 ng · kg-1 · min-1 (WI + ANG II-low), and 3) a seated time control (Con). In another almost identical protocol, 7-10 healthy young males were investigated to delineate the tubular site(s) of action of ANG II by the lithium clearance method (CLi) and were on an additional fourth study day subjected to infusion of ANG II at a rate of 1.5 ng · kg-1 · min-1 (WI + ANG II-high). During WI + placebo, plasma concentration of ANG II decreased from 16 ± 2 to 8 ± 1 pg/ml (P < 0.05) and renal sodium excretion increased from 104 ± 15 to 294 ± 27 µmol/min (P < 0.05). During WI + ANG II-low, plasma ANG II was not suppressed by WI, and the natriuresis was blunted by 52 ± 13% (P < 0.05). During WI + ANG II-low and WI + ANG II-high, an increase in CLi was prevented that was otherwise observed during WI, and fractional distal reabsorption of sodium was facilitated. In conclusion, maintaining plasma concentration of ANG II unchanged at the level of control attenuates the natriuresis of WI considerably in humans. Therefore, suppression of generation of ANG II is an important mechanism of the natriuresis of WI in humans. Furthermore, infusion of ANG II during WI prevents an otherwise induced increase in CLi and facilitates the fractional distal reabsorption of sodium, probably via an effect on aldosterone release.

sodium excretion; tubular function


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THERMONEUTRAL WATER IMMERSION (WI) to the neck in humans induces redistribution of blood from the caudal to the cephalad parts of the body and movement of fluid from the interstitial to the intravascular space. Therefore, central and total blood volume is expanded, which is accompanied by a natriuresis and a diuresis. The generally accepted hypothesis is that the natriuresis and diuresis of WI is initiated by stimulation of cardiopulmonary volume receptors (14). This hypothesis is, however, too simplistic, because we (25) have previously observed that the decrease in plasma colloid osmotic pressure and/or increase in plasma volume per se also might play a role for the initiation of the natriuresis. The natriuresis and diuresis of WI are probably multifactorial in origin and comprise an interaction of cardiovascular, neural, physical, and humoral factors. The quantitative contribution of each of the efferent components is still not defined.

To investigate the qualitative contribution of the renin-angiotensin system to the natriuresis of WI, Epstein and Saruta (16) observed that plasma renin activity and aldosterone were suppressed with very similar temporal profiles. In a later study in anephric humans, Epstein et al. (15) showed that plasma aldosterone was not suppressed by WI. In addition, we (21) have in a recent study shown that plasma ANG II is suppressed by WI. Therefore, results of these studies strongly indicate that suppression of the renin-angiotensin-aldosterone axis is an important mechanism of the natriuresis of WI in humans.

In the present study we tested the hypothesis that suppression of generation of ANG II is a mechanism of the natriuresis of WI in humans. ANG II was intravenously infused to prevent suppression of plasma ANG II by WI, and the effect on the natriuretic response was simultaneously monitored.

In a second protocol, ANG II was infused intravenously in two different amounts on two separate study days during WI to delineate the tubular site(s) of action of ANG II on renal sodium handling by the lithium clearance (CLi) method. The two dosages were used because we at the time of study did not know whether the low level would have any tubular effect.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Studies were carried out in healthy young males. All had a negative history of cardiovascular and kidney diseases and exhibited normal values of routine clinical examinations. All subjects had their urine tested for protein, erythrocytes, and glucose. All tests were negative. All subjects denied taking any medication at the time of the study. The experimental protocols were approved by the Ethics Committee of Copenhagen (V.200.2088/91; KF12-145/99), and after careful oral and written explanation, written consent was obtained according to the Declaration of Helsinki. The experiment fully conforms to the Guiding Principles for Research Involving Animals and Human Beings of the American Physiological Society. The experiment consisted of two almost identical protocols (protocols 1 and 2).

Protocol 1

Eight subjects [age 25 ± 1 yr (SE), weight 76 ± 3 kg, height 1.82 ± 0.02 m] participated in the experiment. No complications occurred.

Each subject was investigated in the upright seated posture during three interventions on different study days with the sequence in a randomized, balanced order between the subjects and separated by at least 4 wk. The sessions consisted of 1) WI to the neck for 3 h with simultaneous infusion of vehicle (WI + placebo), 2) WI to the neck for 3 h with simultaneous low-dose ANG II infusion of 0.5 ng · kg body wt-1 · min-1 (WI + ANG II-low), and 3) a seated time control for 3 h in an empty tank with simultaneous infusion of vehicle (Con). Each session was preceded and followed by the subject being seated outside the water for 1.5 and 1 h, respectively.

For 4 days before each experimental day, the subject was provided with food containing a fixed content of sodium (135-150 mmol/24 h). Twenty-four-hour urine collections were made during the final 2 days of each dietary period. Water intake was ad libitum. No food or fluid intake was allowed for 12 h before the experiment.

From 10:00 PM the evening before the experiment, the subject was confined to the laboratory. He was awakened at 7:15 AM and weighed. A short 18-gauge venous catheter (Venflon, Viggo-Spectramed) was inserted into each cubital vein: one for collection of blood and one for infusion of vehicle and/or ANG II. After emptying the bladder, the subjects drank 400 ml of tap water and were seated (wearing a bathing suit) in a chair. Thereafter, they were subjected to WI or Con. At all times during the experiment (before, during, and after immersion or control), both of the subject's arms were kept resting on a support above the water and always at the same distance above the heart. Arterial pressures were corrected for hydrostatic errors by adding to the recorded pressures the distance from the cuff to the fourth intercostal space divided by 1.36.

WI was performed by lowering the subject by a hoist into an insulated plastic tank, which was empty during Con or filled with tap water during WI. During the pre- and postimmersion periods, the subject sat in the chair above the water. Average water temperature varied over time between 34.5 ± 0.02 and 34.7 ± 0.07°C, room temperature between 25.8 ± 0.02 and 26.2 ± 0.06°C, and relative air humidity between 30.3 ± 1.9 and 44.8 ± 2.07%.

Arterial pressures and heart rate (HR) were determined at half-hourly intervals and cardiac output (CO) and left atrial diameter every hour. A total of 300 ml of blood was collected during the experiment according to the time intervals indicated in Fig. 1 and Table 1. Before each blood sampling, 2 ml of blood were drawn to empty dead space. After each sampling of blood, the catheter was flushed with an amount of isotonic saline equal to that of the collected blood. Finally, at hourly intervals the subjects stood briefly on a support to empty the bladder and thereafter drank 200 ml of tap water. Measurements and procedures were always performed in the following sequence: blood sampling, arterial pressures, left atrial diameter, HR, CO, urine collection, and determination of residual urine by ultrasound.


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  		Fig. 1.   Protocol 1: renal sodium excretion (UNaV; A), plasma concentration of ANG II (B), plasma concentration of aldosterone (Aldo; C), and mean arterial pressure (MAP; D) before, during, and after 3 h of water immersion (WI + placebo; ), water immersion and infusion of 0.5 ng ANG II · kg-1 · min-1 (WI + ANG II-low; down-triangle), and a seated time control (Con; ). Values are means ± SE of n = 8. * Significant difference compared with preimmersion value. # Significant difference from other 2 sessions at same experimental point in time. + Significant difference from Con at same experimental point in time.


                              
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  		Table 1.   Plasma hormones and plasma protein

ANG II (Clinalfa, Switzerland) infusion started simultaneously with WI. Subjects received a 3-h intravenous infusion of either ANG II at 0.5 ng · kg-1 · min-1 in 0.9% saline or vehicle (0.9% saline). A 50-ml syringe pump (Braun) delivered the infusion at a rate of 3-4 ml/h. The experiment was performed in a single-blinded fashion.

Plasma concentrations of norepinephrine (NE) and epinephrine (Epi) were measured with a radioenzymatic assay (9). Plasma concentrations of ANG II were measured according to Bie and Sandgaard (4). Plasma aldosterone was measured by radioimmunoassay with a commercially available kit (Coat-A-Count, DPC), and plasma concentration of atrial natriuretic peptide (ANP) was measured by radioimmunoassay (41).

Plasma protein concentration (Pprot) was measured in duplicate in a refractometer (pocket refractometer, Bellingham & Stanley). Concentrations of Na+ and K+ in urine and plasma were measured in fresh samples with an ion-selective electrode system (KNA-2, Radiometer, Copenhagen, Denmark).

Echocardiographic recordings (model SSD 500; Aloka, Japan) of left atrial diameter were obtained using the parasternal long-axis view in M-mode according to the criteria of Feigenbaum (17). Left atrial diameter was determined from the average of three M-mode pictures, which in a blinded fashion were analyzed by the same investigator with regard to all of the subjects.

HR was calculated from electrocardiogram recordings. Systolic, diastolic, and mean arterial pressures (MAP) were measured every half hour in the brachial artery by oscillometry (Propaq 102, Protocol Systems, Beaverton). CO was estimated with a noninvasive inert gas rebreathing technique (AMIS 2001; Innovision, Odense, Denmark) as previously described in detail (6, 10). Total peripheral vascular resistance (TPR) was calculated by dividing MAP by CO.

Residual urine was calculated by the formula described by Roehrborn and Peters (39). Urine volumes were corrected if calculated residual urine exceeded 30 ml. Urine flow rate (V) and renal sodium excretion (UNaV) were calculated by conventional formulas.

Protocol 2

Ten subjects (n = 10) [age 27 ± 1 (SE) yr, weight 84 ± 3 kg, height 1.84 ± 0.02 m] participated in the Con and WI + placebo experiments. Eight of the subjects (n = 8) [age 27 ± 1 (SE) yr, weight 85 ± 3 kg, height 1.85 ± 0.02 m] participated in a high-dose ANG II infusion (1.5 ng · kg-1 · min-1) (WI + ANG II-high) experiment. Seven of the subjects (n = 7) [age 28 ± 1 (SE) yr, weight 82 ± 2 kg, height 1.83 ± 0.02 m] participated in a low-dose ANG II infusion experiment (0.5 ng · kg-1 · min-1) (WI + ANG II-low). None of the subjects participated in protocol 1. At the first experimental day three subjects reported discomfort during catheterization and were therefore excluded. In one subject it was not possible to insert the catheter on one experimental day (WI + ANG II-low), so blood was not sampled at that day. No further complications occurred.

All procedures were the same as in protocol 1, except as follows. 1) LiCO3 (12.15 mmol; 450 mg) was administered to the subjects at 10:00 PM on the evening before the experiment for determination of lithium clearance. 2) Plasma concentrations of ANG II, aldosterone (DSL-8600, obtained from Diagnostic Systems Laboratories, Webster, TX), NE, and Epi were measured by other assays (3, 26). 3) Glomerular filtration rate (GFR) was determined by renal clearance of 51CR-EDTA (Amersham, UK) (7), and plasma and urinary lithium concentrations were determined by atomic absorption spectrophotometry (Perkin Elmer 1100 B, Norwalk, CT) (1). 4) Echocardiography of the left atrium was replaced by central venous pressure measurement. It was measured through a fluid-filled catheter inserted from a cubital vein to the intrathoracic region. 5) Blood was sampled from the central venous catheter. 6) In addition to the infusion of 0.5 ng · kg-1 · min-1, ANG II was also infused at a rate of 1.5 ng · kg-1 · min-1 (WI + ANG II-high).

Renal sodium clearance (CNa) and CLi were calculated as the ratio between the urinary excretion rates and the mean plasma concentrations. The absolute proximal tubular reabsorption rate of fluid (APRFluid) was determined as GFR - CLi. The absolute proximal tubular reabsorption rate of sodium (APRNa) was determined as (GFR - CLi) × PNa, where PNa is plasma concentration of Na. Absolute distal reabsorption rate of sodium (ADRNa) was calculated as (CLi - CNa) × PNa, and fractional distal sodium reabsorption (FDRNa) was calculated as (1 - CNa/CLi). Whole kidney fractional excretion of lithium (FELi) and sodium (FENa) were determined as CLi/GFR and CNa/GFR, respectively.

Statistics

Data are presented as means ± SE. A two-way ANOVA (Statgraphics plus for Windows, version 3.0) for repeated measures with the variable as the main variate and time and subjects as factors was used to evaluate the effects on a variable over time compared with the mean of the preimmersion values within each series of experiment. To evaluate whether there were significant differences between the mean values of the sessions, a two-way ANOVA (GB-stat for Windows, version 5.3) was used with the variable as main variate and sessions and time as factors. Differences between mean values were evaluated by a post hoc multiple-range test (Newman-Keuls). Paired and unpaired t-tests were applied when appropriate. A significance level of 0.05 was chosen.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Protocol 1

Renal variables. Infusion of ANG II attenuated the natriuresis of WI (Fig. 1) because during WI + placebo, UNaV increased from 87 ± 16 µmol/min to a peak of 262 ± 14 µmol/min during the third hour of immersion (P < 0.05), whereas UNaV only increased from 73 ± 8 µmol/min to a peak of 160 ± 30 µmol/min (P < 0.05) during WI + ANG II-low. Cumulative sodium excretion during WI + placebo was significantly different from cumulative sodium excretion during WI + ANG II-low during the 3 h of immersion (39 ± 3 vs. 23 ± 4 mmol/180 min; P < 0.05; paired t-test). Values during Con varied insignificantly between 75 ± 12 and 58 ± 7 µmol/min. Urine volumes were corrected five times for residual volumes.

Mean 24-h UNaV was 120 ± 10, 140 ± 14, and 138 ± 17 mmol on the final days of the 4-day dietary periods preceding Con, WI + placebo, and WI + ANG II-low, respectively [not significant (NS)].

Plasma hormones. Plasma concentration of ANG II (Fig. 1) decreased from 12 ± 2 to 4 ± 1 pg/ml during all of the 3 h of WI + placebo (P < 0.05). During WI + ANG II-low, plasma ANG II was prevented from decreasing. During Con, plasma ANG II increased significantly from 8 ± 2 to 16 ± 3 pg/ml (P < 0.05).

Plasma aldosterone decreased during the second and third hour during WI + placebo (Fig. 1), whereas it only decreased during the third hour during WI + ANG II-low (P < 0.05). Therefore, the temporal profile of plasma aldosterone suppression was attenuated by ANG II infusion. During the second hour of WI + placebo, plasma aldosterone was significantly different from the value during WI + ANG II-low (Fig. 1).

During WI + placebo, plasma ANP increased significantly (Table 1). During WI + ANG II-low, plasma ANP was only significantly increased during the second hour. Plasma ANP during WI + ANG II-low did not differ from the values during WI + placebo (NS). During Con, plasma ANP decreased significantly.

Plasma concentrations of NE and Epi were suppressed by WI + placebo and WI + ANG II-low (Table 1, P < 0.05).

Plasma proteins and electrolytes. WI + placebo and WI + ANG II-low suppressed plasma proteins significantly throughout the immersion period (Table 1). Plasma proteins did not change during Con. During Con, plasma sodium varied insignificantly between 138.4 ± 0.4 and 139.3 ± 0.3 mmol/l, and during WI + ANG II-low, plasma sodium varied insignificantly between 138.4 ± 0.5 and 138.8 ± 0.4 mmol/l. During WI + placebo, plasma sodium increased from 138.8 ± 0.4 to 140.1 ± 0.4 mmol/l (P < 0.05). Plasma potassium decreased during WI + placebo from 4.3 ± 0.1 to 4.0 ± 0.0 mmol/l (P < 0.05). During Con and WI + ANG II-low, plasma potassium varied insignificantly between 4.0 ± 0.0 and 4.2 ± 0.1 mmol/l and between 3.9 ± 0.1 and 4.1 ± 0.1 ml/min, respectively.

Cardiovascular variables. MAP did not change during Con and WI + placebo (Fig. 1) but increased during WI + ANG II-low from 87 ± 2 to 94 ± 2 mmHg during the second and third hours (P < 0.05). CO also increased and TPR decreased during WI + placebo and WI + ANG II-low (Table 2, P < 0.05). CO and TPR were unchanged during Con.

                              
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  		Table 2.   Cardiovascular variables

Left atrial diameter (Table 2) increased similarly during WI + placebo and WI + ANG II-low and was unaltered during Con. Pulse pressure (PP) and HR are presented in Table 2. HR decreased during both WI sessions (P < 0.05), while PP did not change. Left atrial diameter and PP were not different during WI + placebo and WI + ANG II-low (NS).

Protocol 2

Renal variables. UNaV exhibited the same response to WI + placebo, WI + ANG II-low, and Con as in protocol 1 (Fig. 2). During WI + ANG II-high, the natriuresis was abolished (Fig. 2). The temporal profile of CNa and FENa (Table 3) followed that of UNaV as indicated in Fig. 2. GFR did not change significantly during any session (Table 3). Urine volumes were corrected six times for residual volumes.


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  		Fig. 2.   Protocol 2: renal UNaV (A), plasma concentration of ANG II (B), lithium clearance (CLi; C), and fractional distal reabsorption of sodium (FDRNa; D) before, during, and after 3 h of WI + placebo (), WI + ANG II-low (down-triangle), WI and infusion of 1.5 ng ANG II · kg-1 · min-1 (WI + ANG II-high; diamond ), and Con (). Values are means ± SE of 10 subjects during Con (CLi and FDRNa, n = 8), 10 subjects during WI + placebo (CLi and FDRNa, n = 8), 7 subjects during WI + ANG II-low (CLi and FDRNa, n = 5), and 8 subjects during WI + ANG II-high (CLi and FDRNa, n = 7). * Significant difference compared with preimmersion value.


                              
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  		Table 3.   Renal parameters for Protocol 2 

CLi (Fig. 2) increased from 24.8 ± 2.2 to 30.9 ± 2.2 ml/min during the second hour during WI + placebo. ANG II infusion prevented this increase during WI + ANG II-low and WI + ANG II-high. During Con, CLi was also unaltered. APRNa was unchanged during all of the four sessions (Table 3). FELi increased from 0.23 ± 0.02 to 0.26 ± 0.02 during the second and third hour during WI + placebo but did not change during the other sessions (Table 3). ADRNa did not change (Table 3). FDRNa, however, decreased from 0.96 ± 0.01 to a nadir value of 0.91 ± 0.01 (P < 0.05). During WI + ANG II-low, FDRNa decreased from 0.96 ± 0.01 to a nadir value of 0.93 ± 0.01 (P < 0.05). For the five subjects who participated in WI + ANG II-low and WI + ANG II-high, the nadir value of FDRNa was different (P < 0.05, paired t-test). FDRNa was unchanged during WI + ANG II-high and increased slightly during Con (P < 0.05).

Mean 24-h UNaV was 177 ± 11, 167 ± 19, 171 ± 13, and 144 ± 11 mmol on the final days of the 4-day dietary preceding Con, WI + placebo, WI + ANG II-low, and WI + ANG II-high, respectively (NS).

During WI + placebo, V increased from 2.1 ± 0.5 ml/min to a peak of 7.8 ± 0.5 ml/min (P < 0.05); during WI + ANG II-low, V increased from 2.1 ± 0.5 ml/min to a peak of 6.3 ± 0.6 ml/min (P < 0.05). During WI + ANG II-high, V increased from 2.6 ± 0.5 ml/min to a peak of 6.0 ± 0.6 ml/min (P < 0.05).

Plasma hormones, plasma proteins and electrolytes, and cardiovascular variables. As depicted in Fig. 2 and Tables 1-3, the endocrine and cardiovascular responses were very similar to that of protocol 1. It should be noted that ANG II during WI + ANG II-low increased slightly from 18 ± 4 to 35 ± 8 pg/ml (P < 0.05) and increased from 18 ± 2 to 57 ± 10 pg/ml (P < 0.05) during WI + ANG II-high. Values not shown exhibited the same response as in protocol 1, and WI + ANG II-low and WI + ANG II-high did not differ.

Plasma aldosterone was only suppressed during WI + placebo (Table 1). During WI + ANG II-low and WI + ANG II-high, it was apparently not suppressed. Therefore, the temporal profile of plasma aldosterone suppression was attenuated by ANG II infusion.

Protocols 1 and 2

A total of 15 subjects received infusion of ANG II at a rate of 0.5 ng · kg-1 · min-1 (Fig. 3). As can be seen in Fig. 3, UNaV was attenuated during all 3 h of immersion. Simultaneously, infusion of ANG II led to plasma levels similar to that of Con. The natriuresis was attenuated by 52 ± 13% (28 ± 2 vs. 12 ± 3 mmol/180 min, P < 0.05).


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  		Fig. 3.   Protocols 1 and 2: renal UNaV (A) and plasma concentration of ANG II (B) before, during, and after 3 h of WI + placebo (), WI + ANG II-low (down-triangle), and Con (). Values are means ± SE of n = 15. * Significant difference compared with preimmersion value. # Significant difference from other 2 sessions in same experimental point in time.

UNaV before immersion and during Con, WI, and WI + ANG II-low was higher in protocol 2 (lithium pretreatment) than in protocol 1 (P < 0.05, unpaired t-tests).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Our findings demonstrate that when a decrease in plasma concentration of ANG II is prevented, the natriuretic response to WI is attenuated. Therefore, suppression of generation of ANG II is a mechanism of the natriuresis of WI in humans. Furthermore, infusion of ANG II prevented an increase in the end-proximal delivery of tubular fluid, which was otherwise induced by WI, and facilitated the fractional distal reabsorption of sodium, probably via an effect on aldosterone release.

WI-Induced Volume Stimulus

Intravascular and central blood volume expansion induced by WI elicits a natriuresis and a diuresis. It has been debated for years how the WI-induced stimulus is detected (afferent limb) and how the natriuresis is initiated (efferent limb; Ref. 14). Suppression of the renin-angiotensin-aldosterone-axis probably constitutes an important part of the efferent limb (14, 21). Therefore, it was our purpose to evaluate the quantitative significance of suppression of ANG II generation for the natriuresis of WI.

ANG II Clamping

The aim of the present study was to clamp plasma ANG II to the level of seated control during WI and with cardiovascular (Table 2) and endocrine variables (Table 1) left unaffected compared with WI + placebo. Therefore, ANG II was not infused in seated control subjects. The results indicate that suppression of plasma ANG II is a necessity to obtain the full WI-induced natriuretic response. This is in accordance with results of isotonic saline infusion in humans and animals (2, 8, 40, 43).

In protocol 1, the level of plasma ANG II during WI + ANG II-low was below the level of Con (Fig. 1), whereas it was slightly above that of Con in protocol 2 (Fig. 2). Despite these under- and overshootings, the natriuresis was attenuated to a similar extent (56 ± 15 vs. 47 ± 10%). Therefore, these variations in plasma concentrations of ANG II, when WI + ANG II-low and Con of the two protocols were compared, were too small to induce different effects on the kidneys. The different levels, however, of plasma ANG II may theoretically have caused an under- or overestimation, respectively, of the importance of ANG II on the natriuretic response to WI. The combined results, however, indicate that the natriuresis was blunted by 52 ± 13% when plasma ANG II was clamped to the level of Con (Fig. 3).

Plasma ANG II , MAP, and FENa

In protocol 2, there was an increase in FENa and in MAP during WI + placebo (Fig. 1 and Table 2). However, MAP remained unchanged during WI + placebo in protocol 1 (Fig. 1), but plasma concentrations of ANG II were suppressed, which shifts the UNaV-MAP relationship to the left. It is, therefore, a possibility that a pressure-natriuresis is one of the mechanisms of the natriuresis of WI, because even small (4-8 mmHg) increases in MAP may induce large augmentations in FENa (20). It seems unlikely, however, that an increase in MAP induced by ANG II infusion is responsible for an increase in UNaV during WI + ANG II-low (Fig. 1), because Bie and Sandgaard (4) have shown that an increase in MAP induced by ANG II infusion does not induce an increase in UNaV in dogs. Finally, our results are in accordance with the concept that ANG II exerts its dominant role on the kidneys and shifts the UNaV-MAP relationship to the right (20, 28). This notion is supported by the lack of effect of ANG II infusion on CO and TPR (Table 2).

Intrarenal Mechanisms of ANG II

GFR did not change significantly during any of the sessions (Table 3). GFR has once been reported to increase during water immersion in humans (36) but has been reported to remain unchanged in several other experiments (11, 35, 37, 45). No method, however, for determination of GFR can detect small (3-8 ml/min) but physiologically significant changes. Therefore, it cannot be excluded that GFR in fact did increase during water immersion due to a decrease in plasma ANG II and that this increase was reversed by ANG II infusion (24).

To delineate the tubular site(s) of action of ANG II on renal sodium handling, we employed the CLi method. This method relies on the assumption that CLi is a quantitative measure of end-proximal fluid delivery to the thin descending limb of loop of Henle (27, 31). We observed that the natriuresis of WI + placebo was accompanied by a significant increase in CLi during the second hour and that low- and high-dose infusion of ANG II (Fig. 2) prevented the increase in CLi. An increase in CLi during WI and a decrease during ANG II infusion have previously been reported (13, 36, 38). A change in CLi can be explained by a change in GFR, a true change in APRFluid, or both. We were not able to detect any changes in either GFR or calculated APRFluid during WI + placebo, WI + ANG II-low, and WI + ANG II-high (Table 3). Therefore, the mechanism(s) behind the changes in CLi cannot be deduced from our results. Results of previous experiments, however, suggest that GFR and CLi increase in parallel during immersion (36) and that they decrease during ANG II infusion (13, 38). This indicates that there is an effect of ANG II on the renal vasculature but that there is no effect of ANG II on the proximal tubular epithelium (44).

The proximal reabsorption of fluid and sodium are mainly load independent (44). Therefore, changes in APRFluid and APRNa may reflect changes in proximal tubular reabsorption. In the present study we did not observe any evidence of a direct effect of ANG II on proximal tubular reabsorption of sodium as demonstrated by an unchanged APRNa (Table 3). This is in accordance with previous results in humans (13, 38). It is, however, well accepted that ANG II exerts its primary effects on the proximal tubular epithelium (19, 24). Therefore, the lack of change in calculated APRNa during suppression of generation of endogenous plasma ANG II and during ANG II infusion could reflect undetectable changes in APRNa due to variations in the GFR and CLi measurements. It is, however, likely that unchanged transport effects of ANG II on proximal luminal receptors during WI + placebo, WI + ANG II-low, and WI + ANG II-high can explain the unchanged APRNa (30). Boer et al. (5) have demonstrated that proximal intraluminal concentrations of ANG II was unchanged in volume expanded rats, and Quan and Baum (34) have demonstrated that addition of ANG II to proximal tubular fluid did not enhance the proximal reabsorption rate. In contrast, application of angiotensin-converting inhibitors in humans and rats decreased the proximal reabsorption rate (22, 34). Therefore, unchanged transport effects of ANG II on proximal luminal receptors may explain the unchanged APRNa in the present study.

The tubular reabsorption of sodium and water is mainly load independent, but some load dependence cannot be excluded. Therefore, changes in FELi may indicate an effect on the proximal tubular epithelium. We are, however, of the opinion that APRNa and APRFluid are the best suited to reflect biological effects in the proximal tubular epithelium. FELi increased during WI + placebo (Table 3). This was prevented by ANG II infusion (Table 3). The increase during immersion and the decrease during ANG II infusion in FELi are in accordance with results of previous experiments (11, 13, 32, 35-38). Thus the prevention of an increase in end-proximal fluid delivery and the prevention of an increase in FELi by ANG II infusion during immersion could indicate an effect of ANG II on proximal nephron sodium balance during WI.

In the integrated distal segments of the nephron, we observed that FDRNa decreased in response to immersion (Fig. 2) but that ADRNa was unchanged (Table 3). A decrease in the FDRNa suggests a decrease in distal reabsorption of sodium due to the load-dependent sodium reabsorption in these nephron segments (48). Infusion of ANG II affected FDRNa in a dose-dependent manner (Fig. 2). Our results are in compliance with previous results of Rabelink et al. (36) who observed a decrease in FDRNa during immersion. Furthermore, FDRNa increases during infusion of ANG II in humans (13, 38). Our data do not allow any firm conclusion based on the statistics on the effect of ANG II on aldosterone release in protocol 2 (Table 1). However, it still remains a possibility that the low level of ANG II infusion attenuated the suppression of aldosterone release, which could have constituted a mechanism of the augmented FDRNa. It is also a possibility that ANG II per se directly affected the distal tubules and thus FDRNa (47).

Our results suggest that the natriuresis of WI in humans depends on an increase in end-proximal fluid delivery and a simultaneous decrease in FDRNa. It is conceivable that end-proximal fluid delivery is regulated by ANG II and that it modulates FDRNa through an effect on aldosterone release (29).

Lithium and Renal Sodium Excretion

The effect of lithium pretreatment on UNaV has been debated for several years (12, 33, 42). To approach reliable plasma concentrations of Li for precise and accurate measurements, a test dose of 450 mg LiCO3 was used in protocol 2 (46). Plasma concentrations of Li reached values between 0.10 and 0.22 mM (data not shown), which should not affect renal UNaV (23). Renal UNaV in protocol 1, however, was significantly lower than renal UNaV in protocol 2. Furthermore, a test dose of 450 mg LiCO3 has previously been found to modulate renal UNaV (33). Therefore, it is likely that lithium pretreatment increased renal UNaV in protocol 2.

Conclusions

Maintaining plasma concentration of ANG II unchanged at the level of control attenuates the natriuresis of WI in humans. Therefore, suppression of generation of ANG II is an important mechanism of the natriuresis of WI in humans. Furthermore, infusion of ANG II during WI prevents an otherwise induced increase in the end-proximal delivery of tubular fluid and facilitates the fractional distal reabsorption of sodium, probably via an effect on aldosterone release.

Perspectives

These data indicate a major importance of ANG II as a mediator of the natriuresis of WI in humans. Previous results from our laboratory indicate that hemodilution is also an important factor. Therefore, the interaction between ANG II and hemodilution during WI should be elucidated in the future. One way to do this is to prevent hemodilution during WI (25) but still suppress plasma ANG II, e.g., by captopril, during WI.

Our data also indicate that at least part of the antinatriuretic effect of ANG II is mediated by an increase in distal reabsorption of sodium. Whether this is a direct effect of ANG II on the distal epithelium or whether it is mediated by an effect through aldosterone release should be investigated, e.g., by ANG II infusion in subjects pretreated with spironolactone.

Finally, the results of this study are also of relevance for understanding pathophysiology of heart disease. Gabrielsen et al. (18) have recently shown that when plasma ANG II is high in heart failure patients, the natriuresis of WI is attenuated. By treating the patients with an angiotensin-converting enzyme inhibitor, the natriuresis of WI was restored to that of normal. Thus WI in combination with modulation of plasma ANG II might be applicable for future studies on mechanisms of disease with fluid volume derangements.


    ACKNOWLEDGEMENTS

The technical assistance of U. K. Larsen, E. Larsen, and B. Kristensen is gratefully acknowledged. The authors are grateful to I. Emanuel for excellent technical assistance during the experiments.


    FOOTNOTES

This project was supported by Danish Research Council Grant 9802910 and by Danish Heart Foundation Grant 96-1-2-33-22378.

Address for reprint requests and other correspondence: P. Norsk, Dept. of Aviation Medicine, Rigshospitalet, Dept. 7522, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark (E-mail: pnorsk{at}rh.dk).

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. Section 1734 solely to indicate this fact.

First published March 22, 2002;10.1152/ajpregu.00536.2001

Received 2 September 2001; accepted in final form 1 March 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Regul Integr Comp Physiol 283(1):R187-R196
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