Clinical Science (1990)78,503-507
503
Renal tubular reabsorption of sodium and water during
infusion of low-dose dopamine in normal man
N. V. OLSEN", J. M. HANSEN?, S. D. LADEFOGEDt, N. FOGH-ANDERSENt
AND P. P. LEYSSAcS
Departments of tNephrology,$Clinical Chemistry and *Clinical Physiology, Herlev Hospital,Herlev, and $Instituteof Experimental
Medicine, University of Copenhagen, Copenhagen, Denmark
(Received 12 June 1989/12 January 1990; accepted 17 January 1990)
SUMMARY
INTRODUCTION
1. Using the renal clearance of lithium (CLi)as an
index of proximal tubular outflow of sodium and water,
together with simultaneous measurements of effective
renal plasma flow, glomerular filtration rate (GFR) and
sodium clearance (C,,), renal function and the tubular
segmental reabsorption rates of sodium and water during
dopamine infusion (3 pg min-' kg-') were estimated in
12 normal volunteers.
2. CN, increased by 128% (P<O.OOl). Effective renal
plasma flow and GFR increased by 43% (P<0.001) and
9% ( P <0.01), respectively. CLiincreased in all subjects
by, on average, 44% (P<0.001). Fractional proximal reabsorption [ 1- ( CLi/GFR)] decreased by 13% after
dopamine infusion (P<0.001), and 'estimated absolute
proximal reabsorption rate (GFR - CLi)decreased by 8 %
( P < 0.01). Absolute distal sodium reabsorption rate
[( CLi- CN,)x PNa,where P,, is plasma sodium concentration] increased (P<0.001), and fractional distal sodium
reabsorption [( cLi
- c N , ) / c L i ] decreased ( P < 0.001).
3. It is concluded that natriuresis during low-dose
dopamine 'infusion is caused by an increased outflow of
sodium from the proximal tubules that is not fully compensated for in the distal tubules.
Dopamine, an endogenous catecholamine, is known to
cause an increase in renal blood flow, glomerular filtration
rate (GFR), urine flow and sodium excretion [l-41. The
rise in G F R and sodium excretion has been interpreted as
a consequence of increased renal blood flow secondary to
an afferent and efferent arteriolar vasodilatation mediated
by the action of dopamine on specific vascular receptors
[4, 51. However, natriuresis after low-dose dopamine has
been demonstrated in the absence of changes in renal
blood flow and GFR, suggesting a specific tubular effect
[2, 6, 71. Recently, specific dopamine DA,-receptors in
the proximal tubule have been identified [8, 91, but
previous studies have given conflicting results about the
proximal tubular effects of dopamine. A n unchanged [6],
an increased [lo, 111 and a decreased [12] sodium reabsorption rate have been suggested by micropuncture
studies and different techniques in vitro.
Segmental tubular transport of sodium and water can
be investigated in man by the lithium clearance (CLi)
method [ 131. Evidence exists that lithium under normal
physiological conditions is reabsorbed in the same proportion as sodium in the proximal tubules and is not
reabsorbed or secreted in the distal tubules [13, 141.
Under these conditions renal CLihas been shown to correlate reasonably with the delivery of sodium and water
from the proximal tubules into the thin descending loop
of Henle in experimental animals [15-171. Indirect
evidence obtained by drug effect studies suggest a similar
tubular handling of lithium in man [13, 181, and distal
tubular reabsorption of lithium, suggested by an increase
in CLiafter amiloride treatment, has only been found
during extreme sodium depletion [18, 191. Simultaneous
determinations of GFR, Cri, clearance of sodium (CNa)
and urine flow may therefore allow an estimation of the
proximal and distal reabsorption rates of sodium and
water. The CLimethod has not previously been used to
investigate the segmental transport of sodium during
infusion of dopamine.
Key words: dopamine, glomerular filtration, lithium clearance, renal tubular function, sodium, water.
Abbreviations: ADRN,, absolute distal reabsorption rate
of sodium; APR, absolute proximal reabsorption rate; CLi
and C,,, lithium and sodium clearances, respectively;
DTPA, diethylenetriaminepenta-acetic acid; ERPF,
effective renal plasma flow; FDRN,, fractional distal reabsorption of sodium; FEN,, fractional excretion of
sodium; FF, filtration fraction; GFR, glomerular filtration
rate; PFR, proximal fractional reabsorption.
Correspondence: Dr N. V. Olsen, Department of Clinical
Physiology, Herlev Hospital, Herlev Ringvej, DK-2730 Herlev,
Denmark.
504
N. V. Olsen et al.
The purpose of the present study was to evaluate renal
tubular handling of sodium and water during intravenous
infusion of low-dose dopamine (3 pg min-' kg-I) in
normal man by simultaneous determination of the
effective renal plasma flow (ERPF), GFR, CLiand CNa.In
this dose dopamine only has minor, if any, effects on aand p-adrenoreceptors [4].
MATERIALS AND METHODS
Subjects
The study was approved by the regional scientific
ethical committee. Twelve healthy volunteers (seven
males, five females, aged 18-48 years) entered the study
after they had given their informed consent.
Protocol
In each subject the effects of dopamine ( 3 pg min-'
kg-l) were investigated. In addition, in six of the subjects
(four males, two females, aged 25-48 years) the effects of
isotonic glucose (55 g/l) alone were investigated .on
another occasion after an interval of at least 3 days.
Lithium carbonate (600 mg; 16.2 mmol) was given orally
on the evening before each investigation. After an overnight fast, a urine flow of at least 400 ml/h was maintained
by orally administered tap water (200-250 ml every 20
min without initial load). Smoking and intake of caffeinecontaining drinks were not allowed. Except for briefly
standing when voiding, the subjects were confined to bed.
After a 1 h control period (period l ) , an intravenous
infusion (3 ml h-' kg-') of dopamine (60 mg in 1000 ml
of isotonic glucose) or isotonic glucose alone (3 ml h-'
kg-l) was started. The infusion continued during three
1 h clearance periods (periods 2, 3 and 4). ERPF and
GFR were measured by a constant infusion technique
with urine collections, using 1311-hippuranand Y Y m T ~ diethylenetriaminepenta-aceticacid ( yYmTc-DTPA)
[20] in
a total dose of, on average, 0.10 mCi (3.6 MBq) and 0.73
mCi (27.0 MBq), respectively. After an equilibration
period of at least 1 h, renal clearances of '311-hippuran,
YYmT~-DTPA,
lithium and sodium were determined for
periods 1 , 2 , 3 and 4, each calculated from the 1 h urinary
excretion rate and the plasma values from three samples
drawn at the start, the middle and the end of each 1 h
period. The total volume of blood samples in each experiment was 260 ml. Blood pressure (measured manually by
sphygmomanometry)and heart rate were recorded at the
end of each period. Body weight was measured at the start
of period 1 and at the end of periods 2 and 4. Packed cell
volume was measured at the middle of periods 1 and 4.
Urine from all periods was tested for glucosuria by using
Dip-Stix.
Analytical methods
13'I-Hippuranand YYmT~-DTPA
in plasma and urine
were determined in a well-counter. Plasma sodium was
measured with a Technicon SMAC instrument, and
urinary sodium was determined with a Technicon RA
1000 instrument (Tarrytown, NY, U.S.A.). Plasma and
urinary lithium were measured by atomic absorption
spectrophotometry (model 403; Perking-Elmer, Norwalk,
CT, U.S.A.) [13].
Calculations
Reabsorption and excretion rates of sodium and water
were calculated based on the assumption that C,
provides an accurate measurement of the rate of endproximal delivery of fluid and sodium [13]:absolute proximal reabsorption rate (APR)= GFR - CLP Proximal
fractional reabsorption (PFR) was calculated as 1- ( CLi/
GFR). Absolute distal reabsorption rate of sodium
(ADRN,) was determined as ( CLi- CNa)x PNa,where PN,
is plasma concentration of sodium. Fractional distal reabsorption of sodium (FDR,,) was calculated as
( CLi-CNa)/CLi,
and fractional sodium excretion (FEN,)
was determined as CN,/GFR. Filtration fraction (FF) was
calculated as GFR/ERPF.
All clearance values were corrected to 1.73 m2 body
surface area. Date were analysed by analysis of variance
and paired t-tests. All data are expressed as means k SEM.
RESULTS
There were no significant differences between baseline
values (period 1) of any variable before infusions of
isotonic glucose or dopamine (unpaired f-tests). None of
the subjects had glucosuria after any infusion.
During infusion of isotonic glucose, no changes were
observed in GFR, CLior C,, (Table 1). ERPF (Table 1)
decreased significantly in periods 3 and 4, and FF (Table
1) increased in periods 3 and 4. Urine flow (Table 1)
decreased in the last period. Packed cell volume
decreased significantly from 0.420 f0.010 in period 1 to
0.404 f0.010 in period 4 ( P < 0.05). All other variables
remained unchanged during isotonic glucose infusion.
During dopamine infusion, ERPF increased by 43%
and GFR increased slightly, but significantly, by, on
average, 9%. FF decreased by 24%. CLiincreased in all
subjects by, on average, 14 ml/min (44%). Dopamine
caused significant increases in urine flow (31%), C,,
(128%) and FEN, (105O/0). Calculated segmental
reabsorption rates are shown in Fig. 1. APR tended to
decrease, but the change was only significant in period 3
(So/,). PFR decreased significantly by 9%, 13% and 13%
in periods 2, 3 and 4, respectively. ADRN, increased by
42%, and FDRN, decreased by 2% from 96.5% to 94.5%.
Packed cell volume remained unchanged. Mean arterial
pressure decreased from 9 2 + 2 mmHg in period 1' to
91 k 2 (not significant), 87 & 3 ( P < 0.05) and 88 f3
( W 0 . 0 5 ) mmHg in periods 2, 3 and 4, respectively.
Heart rate increased from 62 f 2 beats/min in period 1 to
65 k 2 (not significant),65 k 2 (not significant) and 67 f2
(P<O.O5) beats/min in periods 2, 3 and 4, respectively.
Body weight decreased from 69.3 k 3.3 kg in period 1 to
68.4k3.3 kginperiod 4 (P<O.OOl).
DISCUSSION
Although the main assumptions for estimating proximal
tubular outflow with CLimight be considered as being
Renal function after low-dose dopamine infusion
505
dopamine administration than during dobutamine
administration, despite similar effects on cardiac output,
ERPF and GFR by both drugs [26]. Although specific
dopamine DA,-receptors have been characterized by
radioligand-binding studies in the isolated proximal convoluted tubule of the rabbit [S] and in renal cortical
tubular tissue of the rat [9], the effects of dopamine on
renal tubular sodium transport still remain unclear.
Proximal tubular sodium reabsorption, as measured by a
micropuncture technique, was found to be unchanged
after dopamine infusion in dog kidneys, and it was
inferred that the significantly increased sodium excretion
rate was caused by an effect at a site distal to the proximal
tubule [ 6 ] .A similar conclusion was drawn from micropuncture studies in the rat, in which the APR even
increased after intratubular addition of dopamine [lo].In
isolated proximal tubule cells dopamine stimulated
sodium uptake [ll],but by the technique of microperfusion of isolated pars recta segments of the rabbit
proximal tubule in vitro, addition of dopamine was found
to depress reabsorption rates of sodium and fluid [12].
In the present study in normal humans, CLiwas used as
an index of proximal tubular fluid outflow for calculating
segmental tubular reabsorption rates of sodium and
water. The estimated change in APR after dopamine infusion was so small that, although it transiently reached
statistial significance in period 3, it should not be assigned
any functional significance. Rather, the data suggest that
the significantly increased CLi reflects an increase in
proximal fluid delivery due mainly to the vasodilating
effect of'dopamine (increased ERPF) and the resulting
fulfilled in the present study, where young healthy
subjects with normal sodium excretion were investigated,
the data must be interpreted with some reservations, due
to the lack of direct evidence supporting the validity of
using CLiin man. The possibility, and contribution, of
lithium reabsorption in the loop of Henle cannot be
ignored. Water diuresis, used in the present study to
facilitate urine collection, has been shown not to affect CLi
[21]. Recently, lithium was found to abolish the natriuresis
produced by the dopamine prodrug gludopa [22]. However, in another study lithium did not interfere with
sodium excretion after administration of the dopamine
agonist fenoldopam [23]. In the present study, the sodium
excretion rate more than doubled after dopamine infusion. Thus, although some interaction of lithium with
the effects of dopamine cannot be entirely excluded from
the present data, the renal effects of dopamine remained
significantly expressed.
The present finding of increased ERPF, GFR, urine
flow and C,, during low-dose dopamine infusion is in
accordance with previous investigations in normal
humans [2, 4, 241. A change in renal vascular resistance,
with a predominant efferent arteriolar vasodilatation as
suggested by the decreased FF in the present study, could
explain the increased urine flow and sodium excretion, as
previously proposed [4,5].
However, dopamine can produce diuresis and natriuresis in both humans and experimental animals without
significant changes in renal haemodynamics [2, 6, 7, 251.
Specific tubular effects of dopamine are further suggested
by the finding of greater diuresis and natriuresis during
Table 1. Effects of infusion of isotonic glucose (ISO: n = 6 ) and dopamine (DA; n = 1 2 ) on
ERPF, GFR, FF, CLi,C,, ,FEN, and urine flow ( V)
Baseline = period 1,infusion = periods 2 , 3 and 4. Results are means k SEM.Statistical significance:
*P<O.O5, tP<O.Ol, $P<O.OOl compared with baseline.
Periods..
.
1
2
3
4
ERPF (ml/min)
IS0
DA
511 f 16
4 9 8 f 19
499f 12
648 It 26*
477 f 8*
692 f 27$
468 f lot
711 f 19$
GFR (ml/min)
IS0
DA
112k1
1083~4
112f2
113f3*
112f2
114f4t
111f2
118f4t
FF
IS0
DA
0.237 f0.006*
0.166 f 0.004$
0.221 f0.007
0.218 f 0.007
0.226 f 0.006
0.177 f 0.007$
0.236 f 0.007*
0.166f0.006$
31 f 2
32fl
31 f 2
41 +2$
31 f 2
44f2$
IS0
DA
1.19 f 0.22
1.10 f 0.24
1.24 f 0.24
2.31 f 0 . 3 I t
1.I7 f 0.23
2.48f0.21$
1.06 f0.14
2.5 1 f 0.24$
IS0
DA
1.05 f0.19
1.04 f 0.12
1.11 f0.21
2.05 f0.27t
1.04 It 0.20
2.24 f 0.22$
0.96f0.12
2.13 It 0.2 1$
14f 1
13f1
13+1
17f2t
13f1
17+2*
12fl*
16flt
CLi (ml/min)
IS0
DA
31fl
4 6 f If
CN,(ml/min)
V (ml/min)
IS0
DA
N. V. Olsen et al.
506
7000
3
4000
**
**
I
I
I
i
1
2
3
4
Periods
Fig. 1. Effects of infusion of dopamine ( A ; tz = 12) and
isotonic glucose ( 0 ; tz=6) on APR, PFR, ADRN, and
FDRN, in four consecutive 1 h periods (baseline = period
1; infusion = periods 2 , 3 and 4). Results are means fSEM.
Statistical significance: *P< 0.01, **P< 0.001 compared
with baseline.
increase in GFR. The increased delivery of sodium and
fluid to the distal tubular segments, as inferred from the
increase in CLi,was associated with an increased ADR,,
and a decreased FDR,,. The present data therefore
indicate that sodium excretion increased because of an
increased output of sodium from the proximal tubules
which was not fully compensated for in the distal tubules.
In summary, an intravenous infusion of dopamine ( 3 p g
min-' kg-I) in normal man increased ERPF, GFR, urine
flow and sodium excretion. CLi,used as an estimate of
proximal delivery of fluid, increased in all subjects by, on
average, 44%. PFR decreased significantly, but changes in
APR were too small to be assigned any functional significance. ADR,, increased, but FDR,, decreased. It is
concluded that natriuresis during low-dose dopamine
infusion is caused by an increased outflow of sodium from
the proximal tubules that is not fully compensated for in
the distal tubules.
ACKNOWLEDGMENTS
This work was supported by grants from the Jacob
Madsens and Olga Madsens Foundation, Copenhagen,
and the Elin Hartelius Foundation, Copenhagen.
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