Renal response
to graded
intravenous
pertonic
NM3 infusion
in
pertensive
subjects:dose-related
impairment
in distal
FdaCl reabsorption”
Janos I’. Radb, M.D.
Eva Juhos, M.D.
Ever-t J. Dorhout
Mees, M.D.
Budapest, Hungary, and Utrecht, The Netherlands
Enhanced sodlium excretion after a salt load has
been described as “‘exaggerated natriuresis” (EN)
in patients with various forms of hypertension.‘-4
Its mechanisms and the renal site of impaired
sodium reabsorption have been extensively investigated, but are increasingly controversial in the
recent literature. A primary tubular defect or an
abnormal response to volume expansion were
considered as possibly responsible for the phenomenon9, Xl a.nd alpredominant role was claimed
for both the proximal tubuleP
and the distal
nephron.s-l’ The abnormal renal handling of sodium previously was,thought to be characteristic to
all patients with essential hypertension, but very
recently it was postulated as a feature of renin
suppression.12-‘4 Our preliminary
studies suggested that depression of free water reabsorption
(T&) was a more sensitive indicator of the altered
renal response to acute NaCl loading than EN
itself, becoming more pronounced with increasing
the load. Furthermore, a similar tendency was
found also in the healthy persons when very high
NaCl loads were used. Therefore, the present
work was designed to compare the renal responses
of healthy subjects and “normal renin” essential
From the Department
ry, and the Department
The Netherlands.
Received
for publication
Accepted
for publication
Reprint
Hospital,
requests:
Dr.
XII. Diosarok
*This
study
of Medicine,
Jams Hospital,
of Nephrology,
University
was supported
0002~8703/80/080183
Budapest,
Hospital,
HungaUtrecht,
Oct. 30, 1978.
March
26, 1979.
JBnos
P. Rad6,
Dept.
u. 1, H-1125
Budapest,
by the Dutch
+ 08$00.80/00
Kidney
1980
of Medicine,
Hungary.
Janos
V.
Materials
and
Mosby Co.
methods
Participants.
Studies were performed on 12
patients with uncomplicated essential hypertension (average age: 34.3 + 2.9 (SEM) years) and on
15 healthy volunteers (average age: 23.5 r?~1.9
years). In the Protocol I and II studies (seebelow)
six male and two female healthy subjects and 10
male and two female hypertensive patients participated; Protocol III was performed on four
male and threle female healthy persons. In the
bypertensive groups the elevation of blood pressure was from mild to moderate and all patients
were free from any demonstrable cardiovascular,
renal, or endocrinologiical consequences of longstanding hypertension. Normal renal function
was assessedb,y urine analysis, creatinine clearance, and DDAVl?* concentration test.15 Renovascular hypertension was ruled out by normal
radiorenogram, intravenous pyelogram and in
certain casesby renal arteriogram.
secondary hypertension were excluded by appronriate tests including renal biopsy. Hypertensive
‘l-Desamino-8-D-Argtiinine
Foundation.
The C.
hypertensive patients to graded acute intravenous hypertonic NaCl loading with special reference to changes in the normal relationship
between solute excretion (“osmolal clearance,”
Cosm) and Th+,. From such a comparison we
expected to ex.clude an intrinsic tubular abnormality and to demonstrate that EN is an acute
renal response ,abnormally reset to a lower level in
the hypertensive patients.
vasopressin.
American
Heart
Journal
183
4.75
i-
1.6G
0.68
4.56
2.20
+-
4.78
i
0.3
6.29
2.12
k0
0.36
5.64
a.08
to
5.65
+ o
0.73
'-
7.61
1.3'6
0.95
15.85
i
19.24
0.001
4.20
i
2.9c;
ct.64
14.09iI.73
23.19i"
2.26
6.41
1.87
i
4.95
0.94
+
4.04
f
m.79
-1-
34.48
1.64
1_O
2"
3.50
14.10
3.97
ta
2.57
k
20.76
3.03
0.05
0.001
k"
3.53
z"
5.10
0.52
1.91
x-3
6.98
1.13
i"
4.85
0.85
?a
6.67
i-O
1.33
3.005
-t
0.54
4.14
7.26i
2.04
zk
3.97
3.64
+-
0.70
5.76
10.72
i
1.49
21.7Oi
1.36
4.51
Q.47
2.40
NS
to
6.86
6.98t"
3.21
+'
31.03
+O
3.18
23.65
i
8.54
k0
2.18
1.44
1.59
29.07
_c'
4.00
29.08
3.48
0.01
0.01
0.001
6.38
III)
in
investigations
the
the
Y!.hAarati.ion
i~v~§tigati~~
and wtitten
behe
-e
9.06
1.13
+
14.01
1.13
to
5.57
0.98
to
+ o
ka
2.62
0.01
Q.05
N, = healthy
subjects
(n = 4); M, = hypertensive
patients
(n = 9); ’ = not significant;
p = p < 0.05 (hypertensive
vs normal).
“Moderate”
NaCi load = intravenous
infusion
of 2.92% NaCl during
60 minutes.
During
NaCl loading
= mean of periods
2 to 6.
After loading
= mean of periods
7 to 10. MaxirnaP
change
= mean of individual
maximum
(in a single period
from 3 to 10) minus
Data are presented
as mean +- SEM.
The
2.30
0.41
8.26-t'
1.39
ute ekarance
k
0.80
5.68+
2.99
-c
2.73
1.48
18.1Qc0
baseline.
perio
two 3G minute
JBnos
w
of
was
fu
consent
the study.
elsinki.
The
explained
was obtained
three membess
nature
to
each
during 60 minutes; an intravenous
dose of 4 pg
DDAVP was given at 9 A.m. in additiion to the two
from them. All
sf the hyper-
l/T treatment
was Ilo
but during the whole experiment 500 mU. ilysine~as~~~~ss~~~ per hour were infused ~t~av~nO~$ly~
No baseline periods were run. One Biter 2.5% NaCl
dukng the first two
C1 was infused during the
ether,
854 mEq. Na were
our one 60 minute clear-
venous
catheter
&ma1
y=.58x+.27
response
to IV hypertonic
NaCl
,H NaCl
rz.99..
B
T ?i20
mI/min
A
5
10
15
‘OS&W
20
25
mllmin
under the influence
of a “moderate”
intravenous
NaCl load in
Fig. 1. Relationship
between
Cosm and Q,
healthy
(circles;
N) and in hypertensive
(black dots; El) subjects. A, All TH?, values obtained during and after
intravenous
NaCl loading were plotted
against Cosm. B, Regression
lines of data of baseline
and NaCl studies.
Note the significant
difference
between
the slopes in the hypertensive
group (solid line, baseline extrapolated)
vs.
no difference
in the healthy
group (dashed
line). Asterisk
= p -C 0.05.
Urine and blood samples were analyzed for creatinine, sodium, Ipotassium (in all groups), calcium,
magnesium, phlosphate (in all lbut group N,), and
for uric acid (only in groups N, and N,) by
procedures applied to the Technicon-Autoanalyzer. Chloride was measured by a chloridometer. All
ion clearances were expressed as a percentage of
GFR (creatinine clearance). When calculating Ca
and Mg clearances, it was assumedlGthat 60% of
the total plasma Ca concentration and 70% of the
total Mg concentration underwent ultrafiltration
in the glomerulus. Osmolality was determined by
an Advanced Osmometer; Cosm and T~I,~ were
calculated acciording to standard formulas. In
order to save space in the Tables, contracted data
of periods 1 and 2 (“baseline”) 3 to 6 (“during
NaCl loading”) and 7 to 10 (“after loading”) are
included. For unity, period 6 was included in the
“during NaCl loading” contracted data of Protocols I and II/a, Correlation coefficients and
regression lines were computed by the method of
least squares. Statistical signifficance was deter-
American
Heart
Journal
mined by the paired t test except when digerent
groups were compared; then the unpaired t test
was used. Data are presented as mean t SEM.
Results
Baseline
rehationship
between
CQSRP and
TLp A “normal” relationship between Cosm and
T&, was established during high NaCl intake by
including all baseline values of the healthy subjects (groups N, and N,) and hypertensive
patients (groups II, and II,). The relationship is
expressed
by
the
formula
y = 0.58
X 40.27 (r = 0.99; p < 0.001) in the bealthy
subjects and lby y = 0.63 x -0.03
(r = 0.99;
p < 0.001) in the hypertensive patients. No statistical difference was found between the slopes
(Fig. 1).
Effect of a “‘moderate”
i~~~ave~Q~s
NaCB load
on the baseline
relationship
between
C2osm and
-cl*0
Healthy
subjects (group IV,). The time-course of
changes in Cosm and ThTo can be seen in Fig. 2.
185
2. Time courseof changesin sarate exe
te i&ravenous
P&a loading iI? womar
TfHzo after a high NaCl bad (h) apparently
(m) iduced
expected
changes.
n&m
and free water reabsorption
and in hypertensive
patients.
Note the
ed to cianges in CQSsn an both gonps. ‘
hiuting
and after
decrease in
)’ NaGI load
Fig. 3. Relationship
(group IV,; circles)
between
and “high”
Cosm and ‘I&
NaCl loading
in healthy
a significantly higher level in this group than an
oup N,, but there was no significant difference
Na, Ca, Mg, and P excretion between the
groups (Table 1).
ealthy subjects (group N,, Protocol
II/a).
The
relationship
during high NaCl loading is
expressed by the formula y = 0.26 X + 1.09
(r = 0.56; p < O.OOl). The slope of this Iiine was
ficantly different from that of moderate
g (p < 0.05). The correlation between
Cosm and Tg2, became much less close after a
high NaCl load than after a moderate hoad (Figs.
2 and 3). There was a significant difference
(p < 0.001) between the mean maximum and
minimum TfHzovalues (6.74 t 0.48 ml./minute vs
1.42 + 0.61 ml./minute)
obtained during high
Na@l loading, but without a significant diBerence
between the corresponding mean Cosm values
(15.17 + 1.24 :ml./minute vs 11.92 ?I 1.57 ml./
mmute), suggesting that the rise of Cosm per se
was not responsible for the dramatic decreas
T& (Fig. 2). The risesin fractional Na, M, Ca,
and Cl excretions were significantly higber after
high NaCI loading than after moderate NaCl
loading (Table II; Fig. 4), but there was no
significant difference in P excretions. It is intering that fractional uric acid excretion slightly
creased after moderate NaC!l loading, but significantly increased in response to a high NaC1
load.
It should be noted that during administration
of a relatively high dose of NaCI by slow intrave-
American
Heart
Jownd
subjects
under
the influence
of “moderate”
NaCl
loading
(group IV,; bhck stars).
rims infusion (group N3, Protocol III), the correlation between changes of Cosm and TfIzO
remained excellent, r G=0.99;
Hypertensive patients (gro
b). ‘The reliationship between Cosm and TfIzo (expressed by the formula y = 0.27 x +0.59) was
less close after high loading (r = 0.49; p < 0.85)
than after a moderate load in group
p < 0.001). Thlere was a significant difference
(p < O.OSl) between tke mean maximum and
minimum TR+ values (5.87 -t 0.43 ml./minute vs
0.86 _t 0.59 ml.imi
e), but no significant difference was found in
corresponding mean Cosm
values (Il.09 +: 1.42 d./minute
QS 7.92 + 1.81
ml./minute).
This study cleady shows that acute Na@l
loading may depress Tg2, not only in hypertensive
patientqg. lo but also in heakhy subj
to 3). In earlier studies carried out in
kealthy subjects, this has not be
because during intravenous administration of
hypertonic I?JaC%
solutions there
no evidence
e increasing
for an upper limit of T&l0Y as
delivery from the proximal nephron enhanced
out of the ascending hmb of
owever, in the previous studies
only moderate Na@l doses were use&l8 and the
present results show that degression of TCHzO
seeurred apparently as a dose-related consequence of acute NaCl ina kg. The a~~~~tat~o~
Qf ‘k,o at any rate of distal delivery of NaCI was
significantly less during high NaCl loading than
after moderate NaCl loadmg, suggestmg impaired
4.
e course
h TFi,a during and
**p < 0.01; ***p <
of changes in fraetionai
excretion
after “moderate”
NaCl loading
0.005;
****p
g, uric acid (TJ and phosphate (P) as well as
and “higPa” Na@l load& (square). *p < Q.W5;
of Na, K, Ca,
(circles)
< o.@m.
NaCPreabsQr~tiQ~in
striking finding wastlhe
in the distal
IllQUSNaCSloads. ur results are in agreement
with those 0
u&es of t&de
tive role in tlae6
tions7) an acceptable ““proximab marker 9719then
of difference in phos
crate and high NaCl
jT
rt the distal interpretation
aiternative
explanation
f
n of TfHzo wsuld be ins
~~ui~~~rat~o~ in the collecting tubules as a resu%t
e osmotic diuresis or/an
t. This, however, probab
case because osmotic diuresis (Cosm) was not
Renal
higher when the lowest Tc,+, values were measured
than in the presence of the maximal Tc,?, values,
and special care was taken to provide the subjects
with supramaximal amounts of DDAVP’” before
and during the experiment. The persistence of the
close correlation between Cosm and T&TOin group
N, (given not lmuch less NaCl but in slow intravenous infusion) underlined the significance of
the speed of a.cute loading in disruption of the
normal relationship.
Our study confirmed that impaired NaCl transport in Henle’s loop is a normal renal response to
a certain degree of volume expansion.zo In hypertensive persons this response is found even after
relatively small NaCl loadings which do not cause
any distortion in the normal relationship between
Cosm and Tc,?,, in the healthy subject. Therefore
EN in the hypertensives seemsnot to be due to an
intrinsic renal tubular defect but is probably the
consequence o:f a basically normal renal response
reset to a lower level.
It was concluded that: (1) impaired distal NaCl
reabsorption may also occur in response to acute
NaCl loadings in the dehydrated healthy subject,
and (2) EN is a.normal renal response abnormally
reset to a l’ower level in the hypertensive
patient.
Heart
Journal
NaCl
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hypertensive paltients.
Summary
The effects of graded acute intravenous hypertonic NaCl loads on the baseline relationship
between osmolal clearance and free water reabsorption established during high NaCl dietary
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