Clinical Science (1985) 69, 293-298
293
Effect of indomethacin on urine concentration and dilution in
the rat
C. R A Y , S. L. CARNEY
AND
A. H. B. GILLIES
Faculty of Medicine, University of Newcastle, Newcastle, New South Wales,Australia
(Received 30 October 198411I February 1985; accepted 3 April 1985)
Summary
1. The precise role of prostaglandins in modulating urine concentration and dilution is unclear.
Evidence in vitro has recently cast doubt on the
accepted theory that renal prostaglandins inhibit
the hydro-osmotic effect of vasopressin.
2. Urine clearance studies were performed on
indomethacin treated (prostaglandin deficient) and
control anaesthetized water diuretic rats both
before and during the addition of vasopressin in
maximal (10m-units) and supramaximal (100
m-units) concentrations.
3. Before the addition of vasopressin, indomethacin treatment inhibited the excretion of a
water load by 48.7%. The mean papillary sodium
concentration was also greater in this group of
rats.
4. Vasopressin (10 m-units) increased the urine
osmolality in control and indomethacin treated
rats; however, the mean urine osmolality was
greater in the indomethacin group (1521 f 103
compared with 1120 98 mosmol/kg; P < O.Ol),
as was the papillary sodium concentration. A tenfold increase in vasopressin depressed the papillary
sodium concentration to a level similar to that in
the control group and produced a marked natriuresis. Consequently, the mean urine osmolalities
and urine flows were similar in control and indomethacin treated rats.
5. These experiments suggest that a major
function of renal prostaglandins is to increase the
ability of the kidney to excrete a water load.
Renal prostaglandins do not interfere with the
vasopressin induced increase in distal nephron
water permeability.
*
Correspondence: Dr S. Carney, Department of
Medicine, Maddison Building, Royal Newcastle
Hospital, Newcastle, New South Wales, 2300,
Australia.
Key words: counter-current mechanism, indomethacin, potassium, prostaglandins, renal
function, sodium, urine concentration, urine
dilution, vasopressin.
Introduction
Although evidence has accumulated over recent
years suggesting that prostaglandins play a role in
modulating mammalian urinary concentration and
dilution, their precise role remains controversial.
Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs potentiates vasopressin stimulated antidiuresis in experimental
animals and man [l-51. The hypothesis that
prostaglandins therefore inhibit the hydro-osmotic
effect of vasopressin is supported by some studies
in vitro. Grantham & Orloff [6], using isolated
rabbit collecting tubules, showed that prostaglandin (PG) El antagonized vasopressin stimulated
water permeability; however, PGEl is not a renal
medullary prostaglandin. Other studies in vitro
with toad bladder and WEz, a principal renal
prostaglandin, have also supported this concept
[7-91. In contrast to the above studies, Ray &
Morgan [lo] in the isolated rat papillary collecting
duct found that PGE, stimulated water permeability and did not interfere with vasopressin
induced water permeability.
Several other factors apart from the action of
vasopressin are important in urine concentration
and may be altered by prostaglandins, including
glomerular filtration rate, proximal tubule
function, salt reabsorption in the thick ascending
limb of the b o p of Henle, medullary urea
recycling, and medullary blood flow. Although it
is unlikely that prostaglandins significantly impair
proximal tubule function [ll], prostaglandins
have been demonstrated to inhibit distal nephron
salt transport at the medullary segment of the
294
C. Ray et al.
thick ascending limb of the loop of Henle [ 12-14],
the cortical collecting tubule [15, 161 and the
collecting duct [ 171. Also, prostaglandins may
reduce rat collecting duct urea reabsorption [18].
Supporting these studies is evidence that inhibition
of prostaglandin synthesis increases renal papillary
solute concentration [ 19, 201. Prostaglandin
induced renal and intrarenal haemodynamic
changes have also been described [21-241.
Because of the difficulties in assigning prostaglandins a precise role in renal concentration and
dilution, clearance studies were performed in rats
to further study the effect of a prostaglandin
synthetase inhibitor, indomethacin, on this
process.
Methods
Animals
Male and female Wistar rats fed on a normal
laboratory diet and weighing between 230 and
270 g were used. Inactin (100 mg/kg intraperitoneally) was used for anaesthesia in nonfasted animals whose body temperature was maintained at 37'C. After tracheostomy, the left
jugular artery and vein were cannulated with
polyethylene tubing (PE-50) and the bladder was
also cannulated through a small abdominal
incision.
Protocol
Animals were infused with a 5% glucose
solution at a rate of 30 ml h-' kg-' body weight to
produce a diuresis. ["CrIEDTA was added to the
infusate to measure glomerular filtration rate. In
some animals this solution also contained indomethacin, infused at a rate of 2 mg h-' kg-' body
weight. After an equilibrium period of 2 h from
the start of the infusion, two 15 min urine collections were made and a midpoint blood sample
taken. Then, either of the following concentrations of arginine vasopressin was added to the
infusion: 10 m-units prime and per hour (maximal
dose), or 100 m-units prime and per hour (supramaximal dose). Urine was then collected for three
further 15 min periods and a midpoint blood
sample taken. Work in our laboratory has shown
that under similar conditions 10m-units of
arginine vasopressin produces a maximum increase
in urine concentration as well as a maximum
reduction in urine flow. Doses of indomethacin
comparable with that used in these experiments
have been shown to depress by approximately
95% the urinary excretion of PGE2 and PCF,,
in volume expanded anaesthetized rats [4, 121.
Also, similar doses of indomethacin do not appear
to alter renal papillary cyclic AMP phosphodiesterase concentrations [4].
Determination of papillary electrolyte concentrations
Just before the addition of vasopressin (10 or
100 m-units), and 30 min after, the kidneys were
removed from groups of anaesthetized rats and the
papillae quickly dissected free. Tissue electrolyte
concentrations were measured by the method of
Gardner & Vierling [25].
["CrIEDTA levels were counted on a gamma
counter (Packard), urine and plasma sodium and
potassium concentration were measured on a
flame photometer (Corning), and urine and plasma
osmolalities were measured on a micro-osmometer
(Wescor Advance Instruments).
Statistical analysis
Probability values were analysed by using
Student's t-test (paired and unpaired) and results
are presented as means f SEM.
Results
During the water diuresis period, the results of the
two consecutive urine collections were similar
and therefore the following results represent mean
values. There were 22 rats in both the control and
indomethacin groups. Urine flow was reduced by
48.7% in the indomethacin treated group (Table 1)
and urine osmolality was significantly greater in
this group (251 ? 29 compared with 156 k 11
mosmol/kg). Free water clearance was therefore
markedly depressed in the indomethacin group.
Pretreatment with indomethacin significantly
reduced sodium and potassium excretion by 46%
and 33% respectively and osmolar clearance was
also numerically, but not statistically, less than
control values. Mean glomerular filtration rate was,
however, similar, being 1.68 ? 0.21 and 1.55 ?
0.43 ml/min in the control and indomethacin
groups respectively.
Analysis of papillary solute concentrations
during this water diuretic period showed that the
mean concentrations of sodium and potassium
were increased by indomethacin treatment
(Table 1).
When a maximally effective dose of arginine
vasopressin was infused (1 0 m-units), a marked
reduction in urine flow and a marked increase in
urine osmolality occurred in both indomethacin
treated and control rats. However, the mean
maximum urine osmolality reached in the indo-
Indomethacin and renal function
295
TABLE1. Effect o f indomethacin in water diuretic rats
Uosm., Urine osmolality; U V , urine flow; Cosm., osmolar clearance; CH 0 , free water
clearance; UVN, and UVK, urine sodium and potassium excretion; GFk, glomerular
filtration rate; papillary Na and papillary K, papillary sodium and potassium concentrations; n , number of rats or papillae. Statistical analysis by unpaired t-test.
~
Uosm. (mosmol/kg)
UV (pl/min)
Cosm. (rosmol/min)
CH,O W/min)
U V N ~(pmol/min)
UVK (rmol/min)
GFR (ml/min)
Papillary Na (mmol/l)
Papillary K (mmol/l)
Control
(n = 22)
Indomethacin
(n = 22)
P
156fll
1 s t 10
89t6
69t6
0.89t0.10
0.48 t 0.04
1.7t0.2
117t6
48t 1
251 t 29
81t9
74t6
7tl
0.48 t 0.07
0.32t 0.03
1.6 f 0.4
164t 7
54t 1
<0.01
<0.001
N.S.
<0.001
<0.001
<0.01
N.S.
<0.01
<0.01
TABLE 2 . Effect o f 10 and 100 m-units o f arginine vasopressin ( A VP) in indomethacin
treated and control diuretic rats
For abbreviations see Table 1. T&,o, Solute free water reabsorption. These values
represent mean values from the third urine collection period after the addition of
vasopressin. Significantly different from control animals: *P < 0.05; * * P < 0.01.
10 m-units of AVP
Control
(n = 8)
Uosm. (mosmol/kg)
UV (pl/min)
Cosm. (rosmol/min)
T&,O (@l/min)
Gi,oICosm.
UVN~
(rmol/min)
U V K (pmol/min)
GFR (ml/min)
Papillary Na (mmolll)
Papillary K (mmol/l)
1 1 2 0 t 98
24r5
100t9
75t6
0.74 f 0.05
2.6 f 0.5
1.5t0.5
1.8t0.2
132t 7
54t 2
methacin group was significantly greater than that
achieved in the control group (Table 2; Fig. l),
being 1521 ? 103 compared with 1120 2 98
mosmol/kg. Mean papillary sodium and potassium
concentrations were also relatively greater in the
indomethacin group, although papillary solute
concentrations significantly increased after the
administration of vasopressin in both indomethacin treated and control rats. Due in part to
a relatively small although statistically significant
increase in urinary sodium excretion (0.47 2 0.08
to 0.89 2 0.26 pmol/min; P < 0.05), osmolar
was significantly less in the indoclearance (Corn.)
methacin group when compared with Cosm.in the
control group. Solute free water reabsorption
(Tkz0) was also reduced by 24% in this group
Indomethacin
(n = 8)
1521 t 103**
1223*
69t8**
57t7*
0.83 t 0.06
0 . 9 t 0.3*
0.6 t 0.2*
1.6t0.2
2 1 3 t 19**
62t4*
100 m-units of AVP
Control
(n = 8)
Indomethacin
(n = 8)
983 iI 9
24t6
88t 10
64t7
0.73 t 0.06
2.3 t 0.5
1.6 t 0.5
2 . 0 t 0.3
1 6 2 t 22
56t3
1046 f 98
26r6
9 8 i 11
72i 8
0.74t 0.05
1.8 t 0.6
1 . 9 t 0.6
1.7t0.2
178t9
55t2
~ ~ not
. statistically
of rats although T & , O / C ~was
different from that measured in the control group.
A tenfold increase in the vasopressin concentration (100 m-units supramaximal) resulted in
similar mean maximal urine concentrations in both
control and indomethacin water loaded rats.
Papillary solute concentrations were also similar,
as were mean urine flows, Corn., T&,o and urinary
sodium and potassium excretion rates (Table 2).
Analysis of these measured factors suggested that
the 100 m-units concentration of vasopressin
appeared to affect the indomethacin treated group
and reduce the maximum urine osmolality and
papillary solute concentration, without significantly affecting the control group. Results in the
100 m-units vasogressin-indomethacin treated
C. Ray et al.
296
1 :
1500
1
t
.-
t
AVP 100 m-units
Effect of vasopressin (AVP: 10 and 100
m-units) on urine flow, osmolality and sodium
excretion and also papillary sodium concentration
and indomethacin treated
in control (M)
(c+ - - 4)
rats. Significantly different between
control and indomethacin groups: * P < 0.05;
XP < 0.01.
FIG. 1.
group were therefore not statistically different
from the 10m-units control group. Mean
glomerular filtration rates measured after the
addition of both concentrations of vasopressin
were not significantly different, being 1.9 1 k 0.20
and 1.67 2 0.15 ml/min in control and indomethacin treated groups respectively.
Discussion
The reduced ability of the rat to excrete a water
load in the absence of endogenous prostaglandin
synthesis has been described by Stoff et al. [20],
who suggested that medullary prostaglandins may
facilitate the excretion of a water load by one of
the following mechanisms. First, prostaglandins
might decrease distal nephron salt transport and
thereby decrease the papillary solute gradient.
Therefore, as water passes through the collecting
system, less water would be reabsorbed since a
significant permeability to water normally exists
in the absence of vasopressin [26]. Another
possibility is that prostaglandins may decrease
distal nephron water permeability in the absence
of vasopressin. On available evidence, the first
suggestion is most likely [12-17, 19, 20,271. The
second proposition is most unlikely since Grantham & Orloff [6] and Ray & Morgan [lo]
showed that prostaglandins significantly increased
collecting tubule water permeability in the absence
of vasopressin in rabbit and rat respectively. Also,
Ray & Morgan failed to alter basal water
permeability when prostaglandin synthesis was
inhibited by indomethacin.
When a maximal (10 m-units) dose of vasopressin was used, the papillary sodium concentration, a measure of the papillary solute gradient
[25], and the mean maximum urine concentration
were greatest in prostaglandin deficient-indomethacin treated rats. These changes were also
associated with a relative decrease in urinary
sodium excretion. These experiments therefore did
not confirm or refute the generally held belief
that medullary prostaglandins impair vasopressin
induced water permeability. However, a relative
increase in the papillary solute gradient produced
by the inhibition of prostaglandin synthesis should
enhance the excretion of a concentrated urine,
irrespective of any direct tubular effect of prostaglandins upon the action of vasopressin. When a
larger vasopressin concentration was given (1 00
m-units supramaximal), no significant differences
in any of the measured factors were detected.
Rather than shifting the vasopressin dose-response
curve to the left by overcoming any inhibitory
effect of prostaglandins on vasopressin mediated
water transport, this larger concentration of vasopressin appeared to depress urine concentrating
ability in the indomethacin treated group without
having a significant effect on the control group.
In particular, a relative decrease in the papillary
solute concentration associated with a 42%
increase in urine solute was measured. Therefore,
during this experimental protocol, a similar
papillary solute concentration in both control and
indomethacin groups was associated with a similar
urine flow and concentration. The effect of vasopressin on water transport was therefore comparable in both groups of rats. Since supramaximal
concentrations of vasopressin do not further alter
mammalian collecting duct water transport [26],
these clearance studies support the only mammalian experiments in vitro where the effect of a
renal medullary prostaglandin (PGE2) an vasopressin induced water transport was studied [lo].
The observation that 10 m-units of vasopressin
produced a marked increase in sodium and
potassium excretion in control but not in indo-
I n d o m e t h a c i n and renal function
29 7
methacin treated-prostaglandin deficient rats
confirm earlier studies that prostaglandins increase
suggests that the vasopressin induced natriuresis
the ability of the kidney to excrete a water load,
[28, 291 is due to a stimulatory effect of vaso- both in the presence and absence of vasopressin.
These prostaglandin effects on water transport
pressin on prostaglandin synthesis [9, 30-321.
The mechanism by which vasopressin at 100 appear to be mainly due to a depressant effect on
the medullary solute gradient, which in turn may
m-units can overcome the inhibitory indomethacin
be due to a direct tubular effect of prostaglandins
effect on urinary sodium excretion is unclear.
or possibly to an effect on the microcirculation.
Such a large dose of vasopressin may have
increased the substrate for prostaglandin synthesis
enough to overcome the inhibitory effect of indomethacin [33], which is considered to be a 'comReferences
petitive irreversible' inhibitor of prostaglandin
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I