Effects of growth hormone on renal tubular handling of sodium
in healthy humans
Troels Krarup
Hansen1,
Jens
Møller1,
Klaus
Thomsen2,
Erik
Frandsen3,
Rolf
Dall1,
Jens Otto
Jørgensen1, and
Jens Sandahl
Christiansen1
1 Medical Department M (Endocrinology and Diabetes) and
2 Department of Biological Psychiatry, Institute for Basic
Psychiatric Research, Aarhus University Hospital, DK-8000 Aarhus C;
and 3 Department of Clinical Physiology, Glostrup Hospital,
University of Copenhagen, DK-2600 Glostrup, Denmark
 |
ABSTRACT |
To investigate the mechanisms behind the water-
and sodium-retaining effects of growth hormone (GH), we studied the
effect of GH on 1) water and sodium homeostasis,
2) the renin-angiotensin-aldosterone system (RAAS), and
3) lithium clearance (CLi) with and without concomitant prostaglandin (PG) synthesis inhibition with ibuprofen. GH
administration for 6 days induced a significant increase in plasma
renin, which was abolished by coadministration of ibuprofen (mU · l
1 · 24 h
1: control:
22.4 ± 4.3; GH: 37.7 ± 8.8; ibuprofen: 15.2 ± 3.0; GH + ibuprofen: 19.7 ± 2.5; ANOVA: P < 0.01).
Comparable increments in extracellular volume were seen after 6-day
treatment with GH alone and in combination with ibuprofen [liters:
control, 19.57 ± 0.92; GH, 20.80 ± 1.00 (ANOVA: P
< 0.0005); ibuprofen, 19.38 ± 0.90; GH + ibuprofen,
21.63 ± 1.37 (ANOVA: P < 0.0005)]. Treatment with GH increased CLi and changed the tubular handling of
sodium and water. The absolute distal sodium reabsorption was
increased, and this was only partially counterbalanced by decreased
reabsorption in the proximal tubules. The data demonstrate that
GH-induced activation of the RAAS can be blocked by concomitant PG
synthesis inhibition and that the tubular effects of GH include
increased distal nephron sodium and water reabsorption.
sodium metabolism; renin-angiotensin-aldosterone system; lithium
clearance; ibuprofen
 |
INTRODUCTION |
THE MECHANISMS
behind the antinatriuretic and water-retaining effects of growth
hormone (GH) are complex and not yet fully clarified. There is evidence
of a direct sodium-retaining effect of GH on the tubules (1,
17), which is present even in the absence of the adrenals
(19, 29). In addition, several studies have demonstrated
an effect of GH on sodium and water homeostasis via stimulation of the
renin-angiotensin-aldosterone system (RAAS) (7, 13, 16,
24). The extracellular volume (ECV) is increased by GH, and in
one study, blockade of the RAAS with either captopril or spironolactone
prevented this effect (24).
GH administration causes increased glomerular filtration rate (GFR) and
renal plasma flow (RPF) (6), an effect probably mediated
via insulin-like growth factor I (IGF-I) (11, 15). Prostaglandin (PG) synthesis inhibition can block these effects (14, 33), suggesting that GH increases GFR and RPF via
vasodilating PGs. It is not clarified whether the effects of GH on
sodium homeostasis involve PGs. However, intrarenal PGs also stimulate
renin secretion (25); therefore, the effects of GH on
tubular sodium handling may be mediated via PG stimulation of RAAS.
To further elucidate the mechanisms behind the water- and
sodium-retaining effects of GH, we studied the effect of GH on water and sodium homeostasis and on the RAAS with and without concomitant PG
synthesis inhibition in healthy humans. Measurements of lithium clearance (CLi), a method for determining proximal and
distal tubular reabsorption of sodium and water (32), were
included to obtain information about GH-mediated effects on segmental
tubular sodium handling and on the relation of this to RAAS activation.
 |
SUBJECTS AND METHODS |
Subjects.
Eight healthy males volunteered, all with body mass index <25 and a
mean age of 26.1 yr (23-31 yr). The study was approved by the
local ethics committee and the Danish National Board of Health, and
informed consent was obtained from each subject.
Design.
The subjects were examined during four different periods of 6 days each
in random order with 4-wk intervals. During each period, the subjects
received an individually prepared sodium-fixed diet containing 200 mmol
of sodium. The diet was otherwise identical to the subjects' prestudy
diets based on a careful nutritional interview by a clinical dietician.
One period served as a control, whereas the participants during the
other periods received either GH (6 IU/m2 Norditropin, Novo
Nordisk, Copenhagen, Denmark), ibuprofen (400 mg × 3 Ibuprofen
"DAK", Nycomed Danmark, Copenhagen, Denmark;), or GH (6 IU/m2) plus ibuprofen (400 mg × 3). GH
was administered once daily by subcutaneous injections into an
abdominal skinfold at 2000. Ibuprofen was given orally each day at
0800, 1600, and 2400.
During each study period, blood samples were drawn on days
0, 2, 4, and 6 at 0800 after an overnight fast. All
blood samples were drawn after
30 min of rest in the supine position.
The blood samples were analyzed for concentrations of IGF-I, insulin,
renin, aldosterone, and NH2-terminal proatrial natriuretic
factor (proANF). Bioimpedance measurements were done at the same time
(Animeter, HTS Engineering, Odense, Denmark). On days 0 and
6, 24-h ambulatory blood pressure and heart rate were
measured every 20 min during the daytime (0600-2400) and every
hour during the night with a portable automatic monitor (SpaceLabs,
model 90202, Redmond, WA). Twenty-four-hour urinary collections were
made on days 0, 2, 4, and 6 for determination of
sodium and potassium excretions.
On day 5, the subjects were admitted to the clinical
research unit at 2200. The following day, intravenous catheters were inserted into a cubital vein for blood sampling and into an
antebrachial vein on the contralateral arm for infusion of isotopes.
ECV, plasma volume, and GFR.
ECV was determined using 82Br as previously described
(2). 82Br was injected at 0900, and blood
samples were drawn 4 h later. Determination of plasma volume (PV)
was done between 1300 and 1400 by intravenous injection of
125I followed by blood sampling every 10 min for 50 min
(8). GFR was measured using a single injection of
51Cr-EDTA (4).
Lithium and sodium clearance.
On day 5, the subjects received 300 mg of lithium carbonate
(Lithiumkarbonat "Dak", Nycomed Danmark) by mouth at 2200. On day 6, blood samples for analysis of lithium and sodium were
collected at 0900 and 1300, and urine was collected between 0900 and 1300.
Assays.
Sodium and potassium concentrations in serum and urine were
measured by routine methods at the Department of Clinical Chemistry, Aarhus University Hospital. Serum GH was determined by a
time-resolved immunofluorometric assay (TR-IFMA; Delfia,
Wallac, Finland). Serum IGF-I was measured with an in-house TR-IFMA
(10), and insulin analyses were performed by
radioimmunoassay (RIA) as previously described (26).
Plasma and urinary concentrations of lithium were determined by
emission photometry and atomic absorption spectrophotometry, respectively. Plasma renin concentrations were determined with an
antibody-trapping method based on the conversion of exogenous renin
substrate to angiotensin I in the presence of antiserum against this
peptide (24). Plasma aldostrone was measured using a
commercial RIA kit (Diagnostic System Laboratories, Webster, TX), and
NH2-terminal proANF was measured using a commercial
antiserum from Penninsula Laboratories, Belmont, CA (22).
Calculations and statistical methods.
On the basis of the assumptions that lithium is reabsorbed only in the
proximal tubules in the same proportion as sodium and water and that
lithium is not reabsorbed in the distal nephron, CLi
represents the delivery of isotonic fluid at the end of the proximal
tubules. The following estimates of segmental tubular handling of
sodium and water can be calculated using CLi, GFR, sodium clearance (CNa), plasma concentrations of sodium
(PNa) and lithium (PLi), urinary concentrations
of lithium (ULi), sodium (UNa), and
potassium (UK), and urine flow rate (V)
All statistical calculations were done with SPSS for Windows,
version 10.0 (SPSS, Chicago, IL). Twenty-four-hour urinary output
(AUCU), sodium excretion (AUCU-Na), and
potassium excretion (AUCU-K) were calculated as areas under
the curves (AUC) of the measurements at days 0, 2, 4, and 6 according to the linear trapezoidal rule
(20). PVs of renin (AUCrenin), aldosterone
(AUCaldosterone), and NH2-terminal proANF
(AUCANF) were calculated in the same way. Differences
between treatment regimens were tested by analysis of variance with
repeated measurements (ANOVA, general linear model). P
values refer to overall effect of treatment (ECV, PV, CLi,
AUCU, AUCU-Na, AUCU-K) or to the
overall effect of time and treatment (IGF-I, insulin, bioimpedance,
weight, renin, aldosterone, and NH2-terminal proANF).
P values <0.05 were considered significant. When
significant changes occurred, paired t-tests were used for post hoc comparisons. These results are indicated as follows: P < 0.05 compared with the control situation. When
necessary, logarithmic transformations were performed to obtain
normality. All results are expressed as mean ± SE.
 |
RESULTS |
IGF-I and insulin.
Treatment with GH as well as GH in combination with ibuprofen caused a
significant increase in serum IGF-I levels [day 6 (in µg/l): control, 279 ± 27; GH, 636 ± 52 (P < 0.05 vs. control); ibuprofen, 269 ± 13; GH + ibuprofen,
653 ± 64 (P < 0.0001); Fig. 1] as well as in insulin levels
[day 6 (in pmol/l): control, 29.1 ± 3.3; GH,
94.6 ± 29.0 (P < 0.0001); ibuprofen, 28.1 ± 3.0; GH plus ibuprofen, 74.4 ± 18.6 (P < 0.005)].

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Fig. 1.
Serum insulin-like growth factor I (IGF-I) levels during
the control period ( ) and during treatment with growth
hormone (GH; ), ibuprofen ( ), or
GH + ibuprofen ( ). *P < 0.05 vs.
control.
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Renin, aldosterone, and ANF.
GH administration induced a significant increase in plasma renin with a
peak after 2 days, which was completely abolished by coadministration
of ibuprofen. Ibuprofen administration alone reduced the renin
concentrations compared with the control period (Table
1 and Fig.
2A). Similar changes were
observed in plasma aldosterone (Table 1 and Fig. 2B),
whereas plasma NH2-terminal proANF remained unchanged
during all study conditions (Table 1).
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Table 1.
Effect of treatment with GH, ibuprofen, or both on ECV, PV, the
renin-angiotensin-aldosterone system, and urinary electrolyte excretion
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Fig. 2.
Plasma concentrations of renin (A) and
aldosterone (B) during the control period ( )
and during treatment with GH ( ), ibuprofen
( ), or GH + ibuprofen ( ). *P
< 0.05 vs. control.
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Blood pressure and heart rate.
No differences in 24-h mean systolic and diastolic blood pressure were
detected between the different study situations. Heart rate
(s
1) on day 6 was increased after
administration of GH, but not significantly so after treatment with
ibuprofen or GH + ibuprofen [control, 72.0 ± 2.9; GH,
85.0 ± 3.5 (P < 0.01); ibuprofen, 70.8 ± 2.5; GH plus ibuprofen, 79.8 ± 3.5 (P < 0.01)].
Fluid and electrolyte excretions.
The mean 24-h urinary output (AUCU, ml/24 h) decreased
significantly during GH and GH plus ibuprofen treatment (Table 1 and Fig. 3A). The mean 24-h
urinary sodium excretion (AUCU-Na, mmol/24 h) was reduced
during GH treatment (Table 1 and Fig. 3B), and the mean 24-h
urinary potassium excretion (AUCU-K, mmol/24 h) decreased
during both GH and GH plus ibuprofen treatment (Table 1 and Fig.
3C). Serum sodium and potassium concentrations did not
change significantly during the treatment periods (data not shown).

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Fig. 3.
Mean 24-h urinary output (A), mean 24-h
urinary Na+ excretion (B) and mean 24-h urinary
K+ excretion (C) in the control period and
during treatment with GH, ibuprofen, or GH + ibuprofen. *P
< 0.05 vs. control.
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A significant increase in both ECV and PV was seen after GH
administration. Coadministration of ibuprofen did not influence these
changes (Table 1 and Fig. 4, A
and B). During GH and GH plus ibuprofen treatment, the
increments in ECV and PV were reflected in a significant decrease in
bioimpedance and an increase in weight on day 6 (Table
2).

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Fig. 4.
Extracellular volume (ECV; A) and plasma
volume (PV; B) after the control period and after treatment
with GH, ibuprofen, or GH + ibuprofen. *P < 0.05 vs. control.
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GFR, CLi, and renal
tubular sodium handling.
In Table 3, values of GFR,
CLi, PARNa, PFRNa,
DARNa, DFRNa,
DARH2O,
DFRH2O, UNaV, UKV, and V are listed. GFR did not change significantly after any of the
treatment periods. GH administration induced a significant increase in
CLi. Treatment with ibuprofen caused a minor,
nonsignificant decrease in CLi, and compatible with this,
treatment with GH plus ibuprofen caused a smaller increase in
CLi than did GH alone. In the proximal tubules,
PARNa was unaffected by the different treatments. In
contrast, a significant overall effect of the different treatments on
PFRNa was observed, and after treatment with either GH
alone or in combination with ibuprofen, PFRNa was reduced, although not significantly compared with the control period. In the
distal tubules, DARNa and
DARH2O were significantly increased by
treatment with GH, whereas nonsignificant increments were seen after
treatment with both GH and ibuprofen. Treatment with GH alone or in
combination with ibuprofen tended to increase DFRNa, but
these increments were not significant. There was an overall effect of
the different treatments on DFRH2O, but no
significant differences between the control situation and the treatment
periods were disclosed. The proportions of the filtered load of sodium
(GFR × PNa) reabsorbed in the proximal and distal tubules, respectively, were clearly affected by GH. The expected increased reabsorption of sodium was observed only in the distal tubules and was almost completely compensated for by decreased reabsorption in the proximal tubules (Fig.
5). UNaV, UKV,
and V did not change significantly after any of the treatment periods.

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Fig. 5.
The proportions of the filtered load of sodium
[glomerular filtration rate (GFR) × plasma concentration of
sodium (PNa)] reabsorbed in the proximal and distal
tubules, respectively, after the control period and after treatment
with GH. P values were obtained by paired t-test
for control vs. GH group.
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|
 |
DISCUSSION |
In the present study, we investigated the effects of GH
administration with and without concomitant PG synthesis inhibition on
sodium and water metabolism in healthy humans. This is the first study
to document distinct alterations in renal tubular handling of sodium
and water after GH treatment using measurements of CLi.
GH administration for 6 days caused a significant increase in plasma
renin. Concomitant treatment with ibuprofen completely neutralized
these changes, and although measurements of PG synthesis were not
performed, these data indicate that the stimulatory effect of GH on
renin secretion involves synthesis of PGs. This confirms the findings
of previous studies (33); furthermore, parallel changes in
plasma aldosterone were observed in the present study. Our data
demonstrate that the changes in renin and aldosterone concentrations
were more pronounced within the first 2-4 days of GH treatment.
This supports earlier observations that the initial change in RAAS
tends to subside during prolonged GH treatment (16, 21).
So far, reports on the effects of GH on ANF have been conflicting. In
this study, we measured plasma NH2-terminal proANF, which
could provide a more robust index of ANF secretion (12). In a previous study, decreased levels of ANF after 14 days of GH
administration was reported (23), a finding which was
later attributed to IGF-I (22). In the present study,
NH2-terminal proANF remained unchanged during all study
conditions. However, the strength of this finding is limited by the
relatively small study population size, thus leaving unanswered the
question whether ANF is suppressed during GH administration.
Significant increments were seen in ECV and PV after GH administration
both with and without concomitant administration of ibuprofen. Because
the RAAS was completely blocked through PG synthesis inhibition, this
indicates that the sodium and fluid retention was induced independently
of RAAS. These findings are in contrast to those of an earlier study,
in which blockade of the RAAS with either spironolactone or captopril
prevented GH-induced fluid retention (24). In the present
study, the RAAS was blocked to the same extent through PG synthesis
inhibition; nevertheless, the GH-induced fluid retention was not
obliterated. One could speculate as to whether the RAAS blockade is
counterbalanced by a synergistic effect of ibuprofen on the direct
renal actions of GH. It is well known that inhibition of PG synthesis
induces a temporary retention of sodium and water (9), and
many distinct actions of PGs along the renal tubule have been
described, including antagonism of the hydrosmotic effects of
antidiuretic hormone (3) and decreased sodium reabsorption
in the distal tubules (30). It is also worth noting that,
in the present study, the stimulatory effects of GH alone on RAAS
peaked on day 2, whereas ECV measurements were performed on
day 6, when the levels of renin and aldosterone were close
to baseline (Fig. 2A).
The observed decrease in mean 24-h urinary output and mean 24-h urinary
sodium excretion after GH treatment is consistent with the rise in PV
and ECV. The two variables were also reduced during administration of
both ibuprofen and GH, although the decrease of 24-h urinary sodium
excretion did not quite reach statistical significance. Because plasma
renin concentrations and plasma aldosterone were unchanged during
treatment with GH plus ibuprofen, changes in these variables could not
explain the GH-induced sodium and water retention.
From studies using steady-state isotope infusion techniques, it
has been reported that treatment with GH increases GFR (6, 15,
18), whereas administration of PG synthesis inhibitors induce an
acute decrease of GFR (9). However, in the present study
using the single injection method, no overall significant effect on GFR
was observed after the different treatments.
In the kidneys, lithium ions are reabsorbed in the proximal tubules in
the same proportions as sodium and water, whereas no reabsorption
occurs in the distal part of the nephron. Consequently, the renal
clearance of lithium provides an estimate of the delivery of water and
sodium from the proximal tubules (32). From
CLi, measures of tubular handling of sodium and water can
be calculated.
An original observation from this study is the increase in
CLi caused by GH administration. Treatment with ibuprofen
alone caused a minor decrease in CLi, and treatment with
both GH and ibuprofen caused a smaller increase in CLi than
treatment with GH alone. The decrease of CLi after
ibuprofen may well be due to interference with the measurements of
CLi, as PG synthesis inhibition has been reported to cause
reabsorption of lithium distal to the proximal tubules
(32). Consistent with this, the differences in
CLi between the control and GH treatment periods are of the
same order of magnitude as they are between the ibuprofen and ibuprofen
plus GH periods. This implies that the GH-induced change in
CLi is, in fact, unaffected by concomitant ibuprofen treatment.
The increase in CLi and the decrease in PFRNa
after GH administration are most likely due to an increase of ECV,
which is known to be a major determinant of proximal tubular fluid
output (CLi) through its influence on the vascular filling
pressures (31). Insulin has well-known antinatriuretic
effects (27), and because insulin concentrations were
significantly increased during both GH and GH plus ibuprofen treatment,
one could speculate as to whether the observed changes in
CLi could be mediated through insulin. In a study of
insulin action on kidney function with the use of the euglycemic clamp
technique, however, CLi remained unchanged with increased
insulin levels (28). During GH treatment, DARNa was increased, which could account for the decrease
of the mean 24-h sodium excretion, the observed increase in ECV and PV, and the increase of CLi.
The exact mechanisms behind the observed topographic alterations in
sodium handling during GH administration remain unclarified in the
current setup. In rat kidneys, the GH receptor (GHR) and IGF-I receptor
gene expressions are topographically segregated (5). GHR
mRNA is primarily expressed in the proximal straight tubule, whereas
IGF-I receptor mRNA is predominantly expressed in the glomerulus,
distal nephron, and collecting system. Despite the limited number of
subjects in the present study, the data suggest that the sodium- and
water-retaining effects of GH are exerted primarily at the level of the
distal renal tubules. Consequently, these actions of GH could be
mediated via IGF-I.
In summary, we have shown that the GH-induced activation of the RAAS,
at least as judged by measurements of circulating renin and
aldosterone, is transient and can be blocked by concomitant inhibition
of PG synthesis. Furthermore, we conclude that GH administration stimulates reabsorption of sodium and fluid in the distal nephron, which may explain the increased proximal tubular fluid output (CLi) and the observed sodium and water retention.
 |
ACKNOWLEDGEMENTS |
We are indebted to Joan Hansen for skillful technical assistance,
and to Jørgen Marqversen, Department of Nuclear Medicine, Aarhus
Kommunehospital, for providing isotopes. Novo Nordisk A/S, Copenhagen,
Denmark, generously supplied the growth hormone.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: T. K. Hansen, Medical Dept. M (Endocrinology & Diabetes), Aarhus Univ. Hospital, Norrebrogade 42-44, DK-8000 Aarhus C, Denmark
(E-mail: tkh{at}dadlnet.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.
Received 13 February 2001; accepted in final form 3 August 2001.
 |
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