Vol. 277, Issue 5, R1444-R1452, November 1999
Effects of a three-day head-down tilt on renal and hormonal
responses to acute volume expansion
Pierre
Mauran1,
Saïd
Sediame2,
Anne Pavy-Le
Traon3,
Alain
Maillet3,
Alain
Carayon2,
Christiane
Barthelemy2,
Guillaume
Weerts3,
Antonio
Guell4, and
Serge
Adnot2
1 Département de
Physiologie de la Faculté de Médecine de Reims, American
Memorial Hospital, F-51092, Reims;
2 Laboratoire d'Explorations
Vasculaires et Métaboliques, Service de Physiologie et
d'Explorations Fonctionnelles, Hôpital Henri Mondor et Institut
National de la Sante et de la Recherche Medicale U-492, 94010 Creteil; 3 MEDES/Institut de
Médecine et de Physiologie Spatiales, Clinique Spatiale,
Centre Hospitalier et Universitaire Rangueil, 31403, Toulouse Cedex
4; and 4 Centre National
d'Etudes Spatiales, 75-039 Paris, Cedex 01, France
 |
ABSTRACT |
To clarify whether exposure to 6°
head-down tilt (HDT) leads to alterations in body fluid volumes and
responses to a saline load similar to those observed during space
flight we investigated eight healthy subjects during a 4-day, 6°
HDT and during a time-control ambulatory period with cross-over.
Compared with the ambulatory period, HDT was associated with greater
urinary excretion of water and sodium (UV,
UNaV) from 0 to 12 h (cumulated UV
1,781 ± 154 vs. 1,383 ± 170 ml,
P < 0.05; cumulated
UNaV 156 ± 14 vs. 117 ± 9 mmol, P < 0.05), and with higher
plasma atrial natriuretic factor (ANF) at 4 h. Hemoglobin and
hematocrit increased over the first 24 h, and blood and plasma volumes
were decreased after 48 h of HDT (P < 0.05). Plasma renin activity (PRA) and aldosterone did not differ
between the two groups. With prolongation of HDT, UV and
UNaV returned close to baseline
values. On the fourth HDT day, a 30-min infusion of 20 ml/kg isotonic
saline was performed, while a large oral water load maintained a high
urine output. The ambulatory period experiment was done with the
subjects in the acute supine posture. Sodium excreted within 4 h of
loading was 123 ± 8 mmol during HDT vs. 168 ± 16 mmol during
the ambulatory period (P < 0.05).
The increase in plasma ANF and decrease in PRA were greater during HDT
than during the ambulatory period (ANF 30 ± 5 vs. 13 ± 4 pg/ml,
P < 0.05; PRA 
1.4 ± 0.4 vs. 0.5 ± 0.2 ng · ml
1 · h1,
P < 0.05). Our data suggest that
after a 3-day HDT period, thoracic volume receptor loading returns to
the level seen in the upright position, leading to blunted responses to
volume expansion, compared with acute supine control.
microgravity; body fluids; renal function; hydromineral balance; fluid-regulating hormones; central blood volume
| |
INTRODUCTION |
THE COMPLETE LOSS of hydrostatic forces (weightlessness
or microgravity) that occurs during space flights results in
cardiovascular deconditioning responsible for a decrease in orthostatic
tolerance when the subject returns to normal gravitational stress. The
mechanisms underlying this intolerance are not yet clearly understood.
Current hypotheses ascribe a central role to hypovolemia, which has
been the focus of several inflight studies and ground-based experiments simulating microgravity, for instance using head-down tilt (HDT).
In the well-hydrated human being on earth, blood volume and its
distribution are appropriate for spending most of the time in the
upright posture in a single-gravity environment. Weightlessness and
simulated microgravity have been shown to be associated with a
redistribution of body fluids to the thoracocephalic regions and with a
loss in plasma volume (3, 12, 17, 22). HDT has been widely used to
simulate the microgravity-induced redistribution of body fluids (10,
15, 16), and several studies have shown increases in urine flow rate
(UV) and urinary sodium excretion rate
(UNaV) during the early phase of
HDT (13, 19). However, studies of the renal responses to an isotonic
saline load performed in space (18) and similar studies conducted
during prolonged HDT (6) have brought discrepant results that question
whether HDT is a reliable means of simulating weightlessness.
Norsk et al. (18) compared the responses to a saline load performed
during Space-Lab D2-mission (4-6 days after launch) to similar
ground-based experiments performed in the acute supine and in the acute
seated postures. The microgravity-adapted renal responses to infusion
reflected a condition in between that of ground-based seated and supine
postures: renal sodium and water excretory responses to saline infusion
during flight were increased compared with those observed on earth in
the seated posture but they were delayed and attenuated compared with
those obtained during acute supine ground-based control experiments.
Drummer et al. (6) studied the effects of a 6-day period of
6° HDT on the responses to an intravenous saline infusion of
22 ml/kg body weight. Saline loading was repeated before, during, and
after HDT. The cumulated renal excretion of sodium during the 24 h
after infusion were similar during HDT to the one observed in the acute supine posture before the beginning of HDT. These results are in
contrast with those from Norsk et al. and might indicate that HDT is
not a reliable means of simulating microgravity.
In an attempt to clarify whether the HDT model accurately reflects
exposure to microgravity and to characterize the effects of HDT on
water and sodium handling, we studied changes in renal water and sodium
excretion, plasma volume, and fluid-regulating hormones in volunteers
exposed to a 4-day HDT, as well as their responses to acute
extracellular fluid volume expansion with saline on the fourth HDT day.
For this purpose we used a time-controlled cross-over designed study,
with a saline-loading protocol different from the one used in previous
studies (6).
| |
METHODS |
Subjects.
Eight male volunteers entered the study after giving their written
informed consent. The age range was 23-32 yr [27 ± 1.3 (SD) yr], the weight range was 60-80 kg [70.4 ± 2.6 (SD) kg], and the height range was 170-181 cm [174 ± 1.8 (SD) cm]. All volunteers were healthy, as indicated by
normal comprehensive physical examination, electrocardiogram, stand
test, blood cell count, hematocrit (Ht), hemoglobin (Hb), serum
concentrations of creatinine and electrolytes, blood glucose, human
immunodeficiency virus, and hepatitis B seronegative tests; all had
negative medical and surgical history except for usual benign diseases;
all declared to be nonsmokers and not to use drugs or medications nor
to consume excessive amounts of coffea, tea, caffeinated beverages,
alcohol, and food rich in salt (peanuts, shells, nuocman, etc); all had
on D1 negative blood tests for alcohol and negative urine tests for drugs.
Study design.
Each volunteer participated in two experimental periods, one ambulatory
period and one 4-day HDT period, separated by 2 wk and assigned in
random order. Both experiments were conducted in MEDES
laboratory facilities in Toulouse during the spring. Ambient
temperature and humidity were not controlled; ambient temperature
varied in the range between 20 and 24°C.
The ambulatory period lasted 5 days
(D1 and
D1-D4), during which the volunteers
were ambulatory inside the laboratory during the day, walking in the
lobbies and the halls with occasional sitting with their feet on the
floor. Volunteers were not allowed to lay down during the day, that is
from 0730 to 2100, except for a period in the supine position during
the blood volume experiment on D4.
The HDT period lasted 6 days: during the first day
(D1) volunteers were
ambulatory as previously described. On the second morning after their
arrival at the laboratory, volunteers were allowed to stand up and be
ambulatory for 1 h, which they used for morning toilet and breakfast.
Then the volunteers were placed in a recumbent, 6° HDT
position, in which they remained for the next 4 days
(D1-D4) under continuous video
monitoring. On the morning of D5 they
assumed the upward posture and were asked to spend 1 day more in the
MEDES facilities to verify that they did not experience orthostatic intolerance.
The extracellular fluid volume expansion experiment was done on the
fifth day of each period, that is on HDT
D4.
Caloric intake was 2,500 kcal/day during the ambulatory period and
2,000 kcal/day during the 4-day HDT period. Water intake was 40 ml · kg1 · day1
during both periods. Sodium intake was carefully controlled from the
arrival in the MEDES facilities at 1800 on
D2 and throughout the
experiment. Volunteers were not allowed to eat or to drink anything
other than the meals and beverage given and prepared by the MEDES
staff. They were asked to ingest all food they were given to eat. The
daily intake of water and sodium was kept constant throughout the study
period. Sodium content of beverage and food was calculated from tables
of nutritional values. Meals were prepared so that 6 g of sodium
chloride were used each day. This normal sodium diet was supplemented
with 4 g of sodium chloride (a capsule of 2 g of salt given twice
daily). Thus the daily intake of sodium was kept constant and very
close to 170 mmol. During the week preceding each period the diet was
not controlled but volunteers were asked to abstain from eating food
rich in salt (peanuts, shells, nuocman, etc.) and to supplement their
usual sodium diet with a capsule of 2 g of salt orally twice daily.
Extracellular fluid volume expansion experiment protocols.
Acute extracellular fluid volume expansion with saline was performed as
previously described on the fourth day of each period (1). Each
extracellular fluid volume expansion experiment consisted of a 60-min
equilibration period, a 90-min baseline period
(T90 to
T0) and a 4-h volume expansion period
(T0-T240).
All experiments were conducted in the morning. Volunteers were awakened
at 0730 and had 1 h for their morning toilet and for a light breakfast
(250 ml milk, 10 g sugar, 60 g bread, 10 g butter, 10 g marmalade, 200 ml orange juice) before the beginning of the experiment, and then they
were not allowed to eat throughout the experiment. The ambulatory
volunteers were in the upright or the sitting positions from 0730 to
0830, at which time they were asked to lay down in the supine position
for the beginning of the experiment. The posture of the HDT volunteers
did not change. At 0830 the 60-min equilibration period started. A
catheter was inserted into a superficial vein of both forearms, one for
the infusions and the other for blood sampling. A 15 ml/kg water load
was given orally for 30 min. Indicators infusion was then initiated. At the beginning of the 90-min baseline period
(T90), the volunteers emptied
their bladder and drank 150 ml of water. From then on, at 30-min
intervals throughout the experiment, urine was collected and subjects
drank 150 ml of water. At the beginning of the 4-h volume expansion
period (T0), acute volume expansion
was obtained by infusing 20 ml/kg of isotonic saline over a 30-min
period. Before infusion the isotonic saline was warmed to 37°C by
means of a water bath.
During both the baseline and volume expansion periods, the following
variables were measured: heart rate (HR) and blood pressure (BP) every
10 min, UV and UNaV every 30 min,
effective renal plasma flow (ERPF) assessed based on
p-aminohippurate (PAH)
clearance, and glomerular filtration rate (GFR) assessed based on
inulin clearance at times T0,
T120, and
T240, urine cGMP concentration every
30 min, and blood concentrations of atrial natriuretic factor (ANF) at
T0,
T90, and
T240, aldosterone (Aldo) at
T0,
T60, and T240, and plasma renin activity (PRA)
at T0,
T60, and
T240.
HR and BP measurements.
HR and BP were measured twice daily and every 10 min during the
extracellular fluid volume expansion experiments, using an automatic
sphygmomanometric device (Critikon Dinamap SX/SXP).
Blood volume measurements.
Blood volume was measured using the Evans blue method. The dye was
obtained from the Pharmacie Centrale des Hôpitaux de Paris. Measurements were made on D1
and D3 during the HDT period and on
D3 during the ambulatory period.
Except when placed in the HDT posture, volunteers were resting in the
supine posture during the 15 min preceding the beginning of blood
volume measurement. A catheter was inserted into a superficial vein of
both forearms, one for the dye injection and the other one for blood
sampling. A 9-ml blood sample was taken before dye injection. Evans
blue was injected taking great care not to lose any drop. The catheter was then rinsed with 3 ml of isotonic saline. Blood samples (3 ml) were
drawn at 10, 15, and 20 min after dye injection. The amount of dye
injected was calculated from the difference between the syringe weights
precisely measured before and after the injection. Blood samples were
centrifuged at 3,500 g for 20 min.
Plasma Evans blue concentrations were determined by spectrophotometry
using the preinjection sample as a blank. Plasma Evans blue
concentrations were plotted against time, and extrapolation of the
curve at time 0 gave the virtual
plasma Evans blue concentrations at time
0. The dye injected dose was then divided by the latter
value to obtain the plasma volume value.
Renal measurements.
UV and UNaV were measured daily
during both periods. In addition, on the first and fourth days of each
period, UV and UNaV were measured
at 4-h intervals.
During the extracellular fluid volume expansion experiments, GFR and
ERPF, both corrected for body surface area, were assessed based on
inulin (CIn) and PAH
(CPAH) clearances, respectively. Inulin (Inutest polyfructosant, Boehringer-Mannheim, Mannheim, Germany)
and PAH (Laboratoires SERB, Paris, France) were administered as
previously described (20). After a loading dose of 40 and 10 mg/kg,
respectively, an intravenous infusion was started immediately so that
after 60 min plasma levels remained stable throughout the study. Inulin
and PAH were diluted in normal isotonic saline and infused at a
constant rate of 2 ml/min. Urine collections were obtained by active
voiding at 30-min intervals. Venous blood samples (4 ml) were drawn
before starting the infusions and immediately before the urine
collections at T0,
T90,
T150, and
T240. Urine volume was measured in a
graduated cylinder. Inulin and PAH concentrations were determined using
standard spectrophotometric methods. Values were calculated using the
following standard formulas
where
U and P are urine and plasma concentrations, respectively.
For purposes of comparison, individual mean values for UV and
UNaV were calculated from
cumulated measures obtained at 30-min intervals during baseline periods
and during volume expansion periods. The cumulative sodium excretion
rate was calculated and expressed as the percentage of the sodium load.
Plasma hormone measurements.
One blood sample for each hormone to be assayed was placed in a
polypropylene tube. The tubes were chilled and centrifuged at 3,500 g at 4°C for 20 min. Plasma was
stored at 80°C until the time of the assays.
Plasma hormone measurements (ANF, PRA, and Aldo) were done before HDT,
that is, at 0730 in the supine position on
D1, 4 h after the beginning of HDT on
D1, 24 h
(D2) and 48 h
(D3) after the beginning of HDT and
on the corresponding times of the ambulatory period.
During the ambulatory period, blood samples were obtained with subjects
in the supine position, before standing up in the morning and, for the
second one obtained on D1, after 60 min spent in the supine position. During the extracellular fluid volume expansion experiments performed on D4,
measurements were done at T0 (ANF,
PRA, and Aldo), T60 (PRA, Aldo),
T90 (ANF) and
T240 (ANF, PRA, and Aldo).
Plasma levels of immunoreactive ANF were measured in 6-ml blood samples
collected in chilled tubes containing 10 mg EDTA, 5 mg trypsin
inhibitor, 17.4 mg phenylmethylsulfonyl fluoride, and 0.1 mg aprotinin.
ANF was extracted from 1 to 2 ml of plasma using 0.5 or 1 ml Vycor
glass (Corning Glassware) suspension (60 mg activated glass powder in 1 ml deionized water). The absorbed atrial natriuretic peptide (ANP) was
eluted using 2.5 ml acetone-water. The eluates were transferred to
chilled siliconized glass tubes and evaporated to dryness in a vacuum
centrifuge. The pellet was reconstituted in 0.5 ml buffer
[potassium phosphate 0.1 M, pH 7.4, containing 0.05 M NaCl, 0.1%
bovine serum albumin (RIA grade, Sigma), 0.1% Triton X-100, and 0.01%
sodium azide (Sigma)]. Recovery rate for three different
quantities of ANF added to plasma was 92.5 ± 2.2%. Data were not
corrected for loss during extraction. The antiserum used (Peninsula
Laboratories, RAS 8798, rabbit anti-
-atrial natriuretic polypeptide
serum) was highly cross-reactive with human -ANF (100%), rat ANF
(100%), ANF-(8
33) (90%), rat atriopeptin III (100%), and rat
atriopeptin II (27%). A 0.1-ml aliquot of diluted plasma was added to
antiserum (0.1 ml), and the mixture was incubated at 4°C for 24 h.
On the next day, approximately 7,000 counts/min
125I-ANP (Amersham) was added to
each tube and incubated for a further 24 h. The radiolabel was
separated by addition of 4 mg dextran (0.5 ml) and coated charcoal (0.8 g Norit SXX EXTRA-0.08 g dextran T70 in 100 ml buffer and 5% horse
serum) followed by centrifugation at 2,500 g for 15 min. The assay
IC50 was approximately 25 pg/tube.
PRA and plasma Aldo were measured using 4-ml blood samples. PRA was
indirectly determined based on the generation of angiotensin I
(angiotensin I RIA kit SB-REN-2, ORIS, Gif-sur-Yvette, France) and
expressed as nanograms per milliliter per hour. Plasma Aldo was
determined using a RIA kit (SB-ALDO-2, ORIS) and expressed as picograms
per milliliter.
Urinary cGMP was measured using a commercial RIA kit (cGMP
125I-RIA Kit, Dupont NEX-133).
Other blood tests.
Total Hb was measured by spectrophotometry, using an OSM3 hemoximeter
(Radiometer, Copenhagen, Denmark). Ht was determined using a standard method.
Statistical analysis.
Comparisons were done with two-way ANOVA for repeated measures followed
by protected Fisher's post hoc tests. Differences with
P 
0.05 were considered significant.
| |
RESULTS |
Changes recorded early in the HDT period.
As indicated by the values of 24-h urinary outputs of sodium, the
subjects were in sodium balance (Table 1).
The first 12 h of HDT were associated with an increase in UV and
UNaV, compared with baseline
values and to values obtained during the control ambulatory period
(Fig. 1). Cumulated values of UV and
UNaV were significantly higher
during the first 12 h of HDT than during the corresponding ambulatory
period (cumulated UV 1,781 ± 154 vs. 1,383 ± 170 ml,
P < 0.05; cumulated
UNaV 156 ± 14 vs. 117 ± 9 mmol, P < 0.05). Only during the
first 12 h did UV and UNaV differ
between the HDT and control periods. As shown in Fig. 1, after 24 h of
HDT, UV and UNaV returned to
pre-HDT values and were similar to values recorded during the
ambulatory period (Fig. 1).
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Fig. 1.
Time course of urine flow rate (UV) and urinary sodium excretion rate
(UNaV) during first 48 h of 4-day
head-down tilt (HDT) period and during corresponding part of
time-control ambulatory period (Amb). * Significantly different
from time 0.  Significantly
different from Amb.
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Hb and Ht values increased gradually during the first 24 h after the
beginning of HDT and remained constant thereafter (Fig. 2, Table 2). No changes
were observed during the control ambulatory period. The early changes
in Hb and Ht during HDT were followed by a decrease in blood volume and
plasma volume at 48 h (Fig. 2, Table 2). A decrease in body
weight was also found on the third and fourth days of HDT (Table
1).
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Fig. 2.
Time course of hematocrit (Ht) during first 48 h of 4-day HDT period
and during corresponding part of time-control Amb. Plasma volume (PV)
measured before HDT, 48 h into HDT, and 48 h into Amb.
* Significantly different from time
0. Significantly different from Amb.
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Changes in PRA and in plasma concentrations of ANF and Aldo are shown
in Table 2. Four hours after the beginning of HDT, plasma ANF was
significantly higher than during the ambulatory period. No significant
differences between HDT and the ambulatory period values of PRA and
Aldo were found during the first 48 h of the study.
No significant differences were found for HR and BP values (Table 1).
Effects of 3 days of HDT on responses to a saline load.
Presaline load values of plasma ANF, PRA, and Aldo measured on the
fourth day at T0, that is after water
load and indicators infusion, differed between HDT and the ambulatory
periods. During HDT, lower plasma ANF concentrations and significantly
higher PRA and plasma Aldo concentrations were found compared with
values in the supine control position. No differences were observed for presaline load renal variable values, although there was a tendency toward lower UNaV
(P = 0.12) and ERPF values during the
HDT period than during the ambulatory period (Table
3, Fig. 3).
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Table 3.
Effects of 3-day HDT period on renal responses to acute extracellular
fluid volume expansion achieved using 30-min infusion of 20 ml/kg
isotonic saline
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Fig. 3.
Natriuretic response to saline load performed by means of 30-min
infusion of 20 ml/kg isotonic saline (S), on fourth day of HDT and on
corresponding day of time-control Amb.
UNa, cumulative urinary excretion
of sodium over 4 h after saline load. * Significantly different
from time 0. Significantly
different from Amb.
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During both the ambulatory and HDT periods, extracellular fluid volume
expansion with isotonic saline resulted in increases in
UNaV, plasma ANF, and urinary
cGMP, and in a decrease in PRA (Table 3, Fig.
4). However, the magnitude of the UV and
UNaV increases differed
substantially between the two conditions. The increases in UV and
UNaV from baseline were smaller
during HDT than during the ambulatory control period (Table 3).
Comparing HDT and ambulatory period, the values of
UNaV were similar during the first
2 h after initiation of saline infusion, but thereafter HDT values
decreased and were significantly smaller 3 and 4 h after infusion
(Table 3). During the first 4 h after initiation of the saline
infusion, 123 ± 8.4 mmol of sodium (58.3 ± 4.5% of the sodium
infused) were excreted during the HDT period vs. 168 ± 16.7 mmol
(78.9 ± 7.8% of the sodium infused) during the ambulatory period
(P < 0.05; Fig. 3). No significant
changes were found in ERPF or GFR (Table 3). In both conditions, plasma
ANF values measured 90 min after the beginning of the infusion were significantly increased versus the presaline load value and returned to
the presaline load value within 4 h after the beginning of the infusion
(Fig. 4). The plasma ANF increase was greater during HDT than during
the ambulatory period (30 ± 5 vs. 13 ± 4 pg/ml). Similarly, the
increase in urinary cGMP found 2 h after the infusion tended to be
greater during HDT than during the ambulatory period (Table 3). PRA was
decreased both 1 and 4 h after the beginning of the infusion. The
magnitude of the PRA decrease was greater during HDT than during the
ambulatory period (1.4 ± 0.4 vs. 0.5 ± 0.2 ng · ml1 · h1).
Plasma Aldo kinetics differed between the two periods: Aldo remained
unchanged during the ambulatory experiment and decreased during the HDT
experiment (Fig. 4).
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Fig. 4.
Time course of plasma atrial natriuretic factor (ANF) and aldosterone
(Aldo) concentrations, and of plasma renin activity (PRA) during first
4 h after saline load given as 30-min infusion of 20 ml/kg isotonic
saline, on fourth day of HDT and on corresponding day of time-control
Amb. * Significantly different from time
0. Significantly different from Amb.
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| |
DISCUSSION |
The present study, performed using a cross-over design with a
time-control group, allowed characterization of early renal and
hormonal responses to HDT and responses to a saline load on the fourth
day of HDT. Antiorthostatic HDT bed rest was rapidly followed by
increases in urinary water and sodium excretion and by decreases in
blood and plasma volumes, leading to a reduced natriuretic response to
a saline load. Comparison with a control ambulatory period revealed
that natriuresis occurred mainly within the first 24 h of HDT and was
associated with higher ANF concentrations. On the fourth day of HDT,
and after the water load needed to study renal excretory function, PRA
and plasma Aldo levels were higher and plasma ANF was lower than during
the ambulatory control period, and the natriuretic response to the
saline load was blunted. We suggest that after 3 days of HDT, thoracic
volume receptor loading returns to the level seen in the upright
position, leading to increased activity of sodium-retaining
neurohumoral mechanisms and to decreased renal responses to volume
expansion, compared with ambulatory subjects investigated shortly after
changing from the upright to the supine position.
HDT is used to minimize the gravitational stress exerted on the human
body and thus to simulate exposure to weightlessness. Compared with
results obtained in the supine position just before tilting, HDT has
been shown to induce acute increases in central venous pressure, left
ventricular end-diastolic diameter, stroke volume, and cardiac output,
suggesting a redistribution of body fluid toward the thorax (8, 16,
17). One effect of increased central blood volume (7) is that sodium
and water excretions increase as a result in part of a rise in plasma
ANF and of activation of the low pressure central baroreceptor reflex
(1, 9, 14, 24). It is now well known that loading of the
cardiopulmonary receptors located in the left atrium and pulmonary
circulation induces a decrease in renal sympathetic nerve activity
responsible for renal vasodilatation (and consequently for an increase
in renal blood flow), an increase in
UNaV, and a reduction in renin release (4, 5, 21). An increase in urinary excretion of sodium and
water in response to HDT has been documented in several previous
studies (13, 23), which, however, did not include a cross-over design.
The increases in UV and UNaV have
been shown to be limited to the first day of HDT (13). With
prolongation of HDT, gradual decreases in central venous pressure, left
end-systolic diameter, and cardiac output occurred (8), together with a loss of plasma volume (11). Our data are consistent with this sequence
of events, because we found early increases in UV and UNaV during the first 12 h of HDT
followed by a return to pre-HDT values.
These changes were not associated with a significant increase in plasma
ANF. It is likely that in response to HDT-induced blood shift plasma
ANF concentrations peaked earlier than at the time we chose for blood
sampling, i.e., 4 h after initiation of HDT. However, at this time,
plasma ANF concentrations were significantly higher during HDT than
during the ambulatory period, because of slight, although
insignificant, opposite changes from baseline. For both periods,
baseline values were obtained in the same conditions, that is in the
supine posture, before initiation of HDT and before standing up during
the control period. During the ambulatory period, changing from the
supine position to the upright posture induced a trend toward decreased
plasma ANF concentrations, whereas exposure to HDT induced a trend
toward higher plasma ANF values. After 24 h of HDT, UV and
UNaV values were similar to those
measured during the control ambulatory period, suggesting that a new
steady state was achieved. Plasma volume measured 48 h after starting HDT was lower than during the ambulatory control period. Because Ht and
Hb concentrations were increased as early as 24 h into the HDT period,
it is likely that hypovolemia developed within the first 24 h of HDT,
at the same time as UV and UNaV increased.
If, as it is generally believed, the early increase in
UNaV and the ensuing contraction
in blood volume found a few days after HDT initiation reflects a normal
adaptive process, this should ultimately result in normalization of
central blood volume. If such were the case, a return of thoracic
volume receptor loading to the level seen in control measurements would
normalize PRA, plasma Aldo, plasma ANF, and renal hemodynamics, and
responses to an acute sodium load would be similar after several days
of HDT and during an ambulatory period. In contrast, 3 days after HDT
initiation, and after the water load needed to study renal excretory
function, we found that PRA and plasma Aldo were higher and plasma ANF
lower than at the matching time point during the ambulatory period.
Although ERPF, GFR, and filtration fraction were not significantly
different between the HDT and ambulatory period conditions, there was a
tendency for ERPF to be lower in the HDT than in the control supine
position. In addition, we found that the natriuretic response to a
saline load was less marked on the fourth day of HDT than during the
ambulatory control period. This occurred although plasma ANF and
urinary cGMP concentrations increased and PRA decreased to similar
levels in the HDT and ambulatory conditions. However, cumulative sodium
excretion 4 h after the sodium load was reduced by 26%. Similar
results have previously been obtained by Norsk et al. (18) who compared
responses to a saline load during a Space-Lab D2-mission (4-6 days
after launch) and during ground-based experiments performed in the
supine and sitting positions. They found that sodium and water
excretory responses to a saline infusion were delayed and blunted
during flight compared with those during supine ground-based control experiments. If one examines the relative differences in
UNaV and cumulative
UNa, the attenuation of the renal
response to saline load, compared with acute supine control, seems to
be of smaller magnitude during HDT than during spaceflight.
UNaV was decreased by 40% (0.39 vs. 0.65 mmol/min) in the present study and by 68% (0.14 vs. 0.43 mmol/min) in the study from Norsk et al.; cumulative UNa was decreased by 26% (123 vs.
168 mmol) in the present study and 45% (59 vs. 108 mmol) in the study
by Norsk et al. However, these differences are due to differences in
baseline values. Actually, the absolute decreases in
UNaV and in cumulated
UNa found in space compared with
supine ground-based control experiments were of similar magnitude to
those in the present study (UNaV
0.29 vs. 0.26 mmol/min; cumulated
UNa 49 vs. 45 mmol). However, the
time course of UNaV following
saline infusion was not the same in the two studies. In space the
attenuation of the UNaV response
to saline, compared with supine ground-based control experiments, was
significant 1 h after the saline load (18). In the present study, the
values of UNaV during HDT were
significantly different from those found during the ambulatory period 3 and 4 h after the infusion. Drummer et al. (6) studied the effects of a
6-day period of 6° HDT on the responses to an intravenous
saline infusion of 22 ml/kg body weight. Saline loading was repeated
before, during, and after HDT. Urine flow and sodium excretion were
acutely increased after all infusions, but no significant differences
were found between the three sets of experiments. The cumulated renal
excretion of sodium during the 24 h after infusion were similar during
HDT to the one observed in the acute supine posture before the
beginning of HDT. These results are in contrast with those from Norsk
et al. and with the present ones.
The discrepancy between the present results and those from Drummer et
al. (6) might be due to the differences in the saline loading models
used in the two studies. In the model from the Drummer et al. study,
the volunteers ingested about 100 ml/h of mineral water until 22 ml/kg
saline infusion was initiated. In the present experiments, as in other
studies previously published (1, 14), a large water load was given to
the volunteers (15 ml/kg and then 150 ml at 30-min intervals throughout
the experiment), so as to promote a high rate of urine flow, which is
essential to studies of renal excretory function and of GFR by
clearance methods. The present experimental design provided an ability
to void the sodium greater than in the study of Drummer et al. In the
latter, 3 h after infusion, less than 20% of the sodium infused had
been excreted whatever the experimental condition, whereas in the
present study the corresponding figures were about 60% during the
ambulatory period experiment and 40% during HDT. Although the high
level of hydration we used was an advantage in permitting rather high
sodium outputs, through an increased medullary washout (2), conversely
it probably altered the hormonal responses to the saline load. It
suppressed the arginine vasopressin secretion to undectable plasma
levels, and thus by removing the inhibitory effects of arginine
vasopressin on renin secretion, it may have in turn maintained PRA
higher than what would have been observed without such a large water
load. It is also possible that with high UVs such as those obtained in
the present study, UNaV might be
more dependent on oncotic force gradients and less on hormonal influences than in usual conditions of hydration. Regardless of these
limitations, it should be emphasized that the present results are
concordant with those obtained in space using a saline-loading protocol
comprising a 400-ml water load (18).
The present findings should not be taken as evidence that HDT induces
an excessive loss of plasma, leading to activation of neurohumoral
mechanisms promoting retention of an infused saline load. It is hardly
conceivable that HDT caused natriuresis and that the ensuing decrease
in central blood volume overshot the cardiopulmonary baroreceptor load
level seen in the control supine position. It is much more likely that
the differences in water and sodium handling that we found between the
HDT and ambulatory conditions were related to the body position chosen
as the reference during the control period. Indeed, the choice of the
control body posture is an important point to consider when
interpreting data from experiments dealing with gravitational stress
and volume regulation (17). During the ambulatory period, subjects were studied 2 h after changing from the upright to the supine position. Although such a time interval is usually considered adequate, it may
not be long enough to allow achievement of a new steady state. In
normovolemic subjects, changing from the upright to the supine position
is responsible for a sudden fluid shift perceived by the thorax as a
state of hypervolemia. Thus it is likely that the
UNaV values measured during the
ambulatory period after sodium loading reflected activation of
volume-regulating mechanisms induced not only by the saline infusion
but also by the redistribution of fluid in response to the change in
body position. The ambulatory period
UNaV values obtained during the
first hours following the change from upright to supine may reflect a
nonsteady state of increased central blood volume, whereas data
obtained on the fourth HDT day may reflect a new steady state with a
central blood volume likely to be similar to the one adapted to the
upright posture. The fact that plasma Aldo was decreased by the sodium
load during the HDT period but not during the ambulatory period is
consistent with this hypothesis.
Therefore, using a saline-loading protocol comprising a large water
load, so as to promote high urine and sodium excretion rates, and
different in this regard from the one used in previous studies (6, 18),
which might explain discrepant conclusions, we found that the
natriuretic response to a saline load is blunted by exposure to a 3-day
HDT compared with acute-supine control.
Perspectives
Fluid-regulating mechanisms are designed to maintain a central blood
volume appropriate for counterbalancing the head-to-feet gravity
vector. Given that humans spend about two-thirds of their time in the
upright position, this latter posture may be a more appropriate control
than the supine position in studies attempting to simulate
microgravity. Further studies are warranted including acute seated
control experiments to verify whether renal sodium excretory response
to saline infusion is increased during HDT as it has been shown to be
in space (18).
| |
ACKNOWLEDGEMENTS |
We are indebted to Monique Deriot, Robert Herigault, and
Frédéric Thieffry (Hôpital Henri Mondor,
Créteil) for their technical assistance.
| |
FOOTNOTES |
This study was supported by a grant from the Centre National d'Etudes
Spatiales, 2 place Maurice Quentin, 75-039 Paris, Cedex 01, France.
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: Dr. Serge Adnot,
Laboratoire de Physiologie et d'Explorations Fonctionnelles,
Hôpital H Mondor, 94010 Créteil, France (E-mail:
serge.adnot{at}hmn.ap-hop-paris.fr).
Received 1 July 1998; accepted in final form 21 June 1999.
| |
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