Clinical Science (1994) 86, 399-404 (Printed in Great Britain)
399
Effects of vasopressin VI and V2 receptor antagonists on
progressive renal failure in rats
Hirokazu OKADA, Hiromichi SUZUKI, Yoshihiko KANNO, Yoshitaka YAMAMURA*
and Takao SARUTA
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, japan, and
*Second Tokushimo Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd,
Tokushima, japan
(Received 5 May/22 October 1993; accepted 9 November 1993)
1. The relationship between vasopressin and the progression of renal failure has been proposed, but not
intensively investigated because of a lack of orally
available, selective vasopressin antagonists.
2. The effects of novel, orally available vasopressin
V, and V, receptor antagonists on several indices of
the progression of chronic renal failure, i.e. blood
pressure, urinary protein excretion, sodium balance
and renal histopathology, were investigated by using
Wistar rats with adriamycin-induced nephropathy
accelerated by deoxycorticosterone acetate-salt
hypertension. Groups 2 and 3 were treated with V,
and V, antagonists, respectively, while the untreated
group 1 served as the control. To block the effects of
vasopressin efficaciously, V and V, antagonists were
simultaneously administered (group 4).
3. At week 6, 2 weeks after the beginning of administration of deoxycorticosterone acetate-salt and
vasopressin antagonists after the second injection of
adriamycin, V, and V, antagonists given either alone
or in combination significantly reduced the systolic
blood pressure as compared with the control, and
urine volume was increased in groups 3 and 4. The
proteinuria was also decreased at week 10 in groups
2, 3 and 4. Differences in sodium excretion between
all groups were not significant. Histopathological
alterations in the kidneys of group 4 were significantly ameliorated.
4. These results suggest that a combination of V,
and Vz antagonists can have therapeutic effects in
certain types of chronic renal failure.
,
INTRODUCTION
Excess salt intake can lead to worsening of
hypertension and renal dysfunction in patients with
renal insufficiency, as we previously demonstrated
with an animal model [l]. Although such patients
[2, 31 and salt-induced hypertensive, uninephrectomized rabbits [4] exhibited high serum levels of
vasopressin, the actual role of this hormone in the
progression of renal failure remains controversial
[5-81. The recent development of orally effective,
non-peptide vasopressin V, and V, selective receptor antagonists (OPC-21268 [9-113, OPC-31260
[ l l , 121) has, therefore, permitted an evaluation of
the contribution of vasopressin to the progression of
renal insufficiency induced in experimental animal
models.
In the present study, we describe experiments
performed to determine the effects of these antagonists on the progression of renal injury produced in
rats by a combination of adriamycin-induced nephropathy [131 and deoxycorticosterone acetate
(D0CA)-salt hypertension [14]. Full details of the
model and the effectiveness of each antagonist are
given elsewhere [9-12, 151.
This work was presented at the 25th Meeting of
the American Society of Nephrology, Baltimore,
MD, U.S.A., in 1992.
METHODS
Experimental design
Male Wistar rats (Nippon Rat, Japan), weighing
170& 5 g, were housed in individual metabolic cages,
fed on a standard rat powder-chow (20gIday; 0.38%
NaC1; Oriental Yeast Co. Ltd, Japan) in a deep cup
with negligible spillage and given water ad libitum.
They received two doses of adriamycin (2 mg/kg) via
the tail vein, with an interval of 3 weeks. One week
after the second injection, left nephrectomy was
performed under ether anaesthesia. Intraperitoneal
injection of DOCA (50mg/kg twice a week; Sigma
Chemical Co., Ltd, St Louis, MO, U.S.A.) was then
started, and the standard rat chow was replaced
with a high-salt one (20 g/day; 5% NaCl) containing
the drugs described below for the remainder of the
study [13-151. The rats were randomly divided into
four groups: group 1, control rats without drugs
(n=8); group 2, rats given V, receptor antagonist
(OPC-21268, 200mgday-' kg-'; n=7); group 3,
Key words: glomerular sclerosis, hypertension, proteinuria, renal failure.
Abbreviations: DOCA, deoxycorticosteroneacetate: PAS, periodic acidlschiff's.
Correspondence: D r Takao Saruta. Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo 160, Japan.
400
H. Okada et al.
rats given V, receptor antagonist (OPC-31260,
50mgday-'kg-'; n = 6 ) ; group 4, rats given both
V, and V, antagonists (200 and 50mgday-'kg-',
respectively; n=6). The daily dose of each drug was
chosen on the basis of preliminary studies [9, 121.
Body weight, systolic blood pressure (measured by
the tail cuff method) and 24h urinary volume,
protein, sodium and potassium excretion were measured before and every 2 weeks during the study.
(Urine was collected for 96 h between DOCA injections and processed, and the results were divided by
4.) At week 10, all the rats were killed by decapitation without anaesthesia. Blood samples were
collected for determination of haematocrit, serum
levels of total protein, creatinine, sodium, potassium
and osmality, as well as the plasma concentrations
of vasopressin and the drugs with heparinization.
Urine osmolality was also measured. Kidney tissue
was taken for histopathological examination by
light microscopy.
Group I (n =a). control
Group 1 (n=7), V, antagonist
t Group 3 (n =6). V, antagonist
-D-
-c-
0
2
4
6
Time (weeks)
A
8
10
Fig. I. Changes in systolic blood pressure over 10 weeks. Groups 2, 3
and 4 treated with V, and/or V, antagonists showed significantly lower
blood pressure than the control group at weeks 6, 8 and 10. Statistical
significance: *P <0.05. **P <0.01 compared with the control group. Values
are means +SEM.
Biochemical measurements
Urinary protein was measured by the method of
Lowry et al. [15a]. Serum levels of total protein and
creatinine were determined with an automatic analyser (Fuji Film Co., Ltd, Japan). Urinary and
serum concentrations of sodium and potassium were
measured by flame photometry (JASCO Medical
Instruments, Japan). Osmolality was determined by
freezing point depression (Advanced Instruments,
U.S.A.). The concentration of vasopressin was
measured by radioimmunoassay (Mitsubishi Yuka
Bio-Chemical Lab., Ltd, Japan) after Sep-Pak C,
extraction of plasma [16]. The intra- and interassay coefficients of variation were 8.3-10.3% and
7.8-10.8%, respectively [171. Plasma concentrations
of drugs were determined by h.p.1.c. Briefly, both
drugs were extracted by chloroform, and then condensed and dried. These materials were dissolved in
methanol, and analysed for the products by h.p.1.c.
on a TSK ODS 80 TM (4.6mm x 150mm; Tosoh,
Japan) with CH,Cl,/C,H,OH/H,O
(25:75:1) for
30 min and with CH,Cl,/C,H,OH/H,O
(50:501) as
the mobile phase.
Histopathological examination
The kidney tissue was fixed in 10% neutralbuffered formalin and embedded in paraffin. The
sections were stained with periodic acid/Schiff's
(PAS) stain. Histological alterations were scored as
indices and evaluated semiquantitatively by the
method of Okada et al. [18].
Data analysis
Data are expressed as meansfSEM. One-way
analysis of variance was to determine the significance of difference between groups. Comparisons
between the control and the other groups were by
Dunnett's method, taking P<0.05 as the level of
significance.
RESULTS
Body weight
All rats gained weight throughout the study, and
differences between the control and the other groups
were not significant at the start of the study and
when the rats were killed.
Systolic blood pressure
The systolic blood pressure of the control group
was more than 170mmHg at weeks 6, 8 and 10
(Fig. 1). Significant antihypertensive effects were
observed in group 2, 3 and 4 rats receiving V,
and/or V, antagonists. The lowest pressure was
recorded when both drugs were given (group 4).
Urinary volume and urinary protein excretion
The urinary volume of group 3 and 4 rats
increased abruptly from week 4 (Fig. 2). The urinary
protein excretion of rats in all groups increased
gradually from week 0, but the values were significantly lower in group 4 rats at weeks 8 and 10 and
in group 2 and 3 rats at week 10 (Fig. 3).
Biochemical data
The haematocrit in groups 3 and 4 and the
plasma concentration of vasopressin in group 4
were significantly higher than those of group 1
(Table 1). The serum creatinine level in group 1 was
higher than those of the other groups and was
above the normal range ( I l.Omg/dl, H. Okada et
Vasopressin antagonists and renal failure
200
r
-Q-
-0-
(H. Okada et al., unpublished work), indicating that
the route of administration and the dose of the
drugs were adequate.
Group I @=a). control
Group 2 (n =7). V, antagonist
t Group 3 (n =6), V, antagonist
-o-
401
Group 4 (n=6). V, and V, antagonists
Electrolyte excretion
2
10
8
4
6
Time (weeks)
Fig. 1. Changes in daily urinary volume over 10 weeks. Although the
rats in all groups showed increases in urinary volume from week 4, the V,
antagonist with or without the V , antagonist induced a significant increase
in urinary volume in group 3 and 4 rats compared with the control group
at weeks 6, 8 and 10. Statistical significance: *P<O.OI compared with the
control group. Values are means +SEM.
-c-
Group I (n 4).control
-0-
Group 2 (n =7), V, antagonist
-+- Group 1 (n =6), V, antagonist
-0-
Group 4 (n=6), V, and V I antagonists
All rats in the present study showed a dramatic
increase in sodium excretion at week 6 with little
further change (Fig. 4). These increases paralleled
the increase in sodium intake. However, differences
in sodium excretion between groups were not significant throughout the study, suggesting similar dietary intakes in all the groups. Urinary potassium
excretion increased at week 4 in all groups, but
differences between groups were not significant.
Histopathological examination
In the control rats of group 1 at the time at
which they were killed, focal and segmental to
global glomerular sclerosis/hyalinosis were observed
with moderate arterio/olosclerosis (Figs. 5 and 64.
Localized tubulointerstitial alterations, including
dilated or atrophic tubules containing hyaline casts
and interstitial widening, were noted (Fig. 6 4 .
Simultaneous administration of V, and V, antagonists significantly reduced the degree of histopathological alterations in the kidneys of group 4 rats
(Fig. 6b). The same evaluation of the kidney tissues
of group 2 and 3 rats showed that histopathological
alterations were mildly, but not significantly, attenuated when V, or Vz antagonists were administered alone (Fig. 5).
DISCUSSION
0
2
4
6
Time (weeks)
8
10
Fig. 3, Changes in urinary protein excretion over 10 weeks. Urinary
protein excretion increased gradually from week 0 in the rats of all groups,
but was significantly attenuated in group 2 and 3 rats at week 10, and in
group 4 rats at weeks 8 and 10 compared with the control group. Statistical
significance: *P<O.OI compared with the control group. Values are
means +SEM.
al., unpublished work), but the differences between
the groups were not significant. The serum sodium
concentration was significantly lower in groups 2, 3
and 4 as compared with the control group, as was
serum osmolality (Table 1). On the other hand, all
rats showed almost identical serum levels of potassium. At week 5, urinary osmolality in groups 3 and
4 was already significantly lower than that in group
1 (data not shown), and remained lower until week
10. The urine osmolality in group 2 was significantly
higher than that in groups 1, 3 and 4. The plasma
concentration of each drug in the morning at the
end of study is given in Table 1. The concentrations
were within or slightly lower than the ranges that
have been demonstrated to be effective in uiuo
The roles of vasopressin in progressive renal
insufficiency and the hypertension of chronic renal
failure have been examined by several investigators
[5-81. In addition, blocking the effects of vasopressin with appropriate antagonists has provided
important information concerning the hormonal
functions of this hormone [19-211. It was demonstrated that an elevated level of vasopressin plays an
essential role in DOCA-salt hypertension and contributes to the development of systemic hypertension based on its renal tubular and vascular
effects [14, 22-25] in spite of down-regulated vasopressin receptors [26]. In the present study, we
combined adriamycin-induced nephropathy with
DOCA-salt hypertension [13-1 51, in which vasopressin is presumed to contribute to nephropathy as
well as hypertension.
The results observed in groups 2 and 3 as compared with those in group 1 indicate that the
progression of renal failure depended on both V,
and Vz agonism in this model. Therefore, at the end
of study, the rats in group 4, which received V, and
V, antagonists to block vasopressin receptors, were
the least affected in terms of hypertension, proteinuria and renal histopathological alterations. In
H. Okada et al.
402
Table 1. Biochemical variables a t the end of the study. Values are means +SEM. Statistical significance: *P<0.05, **P<O.OI
compared with the control group.
Group
Haematocrit Serum
protein
concn.
(g/dl)
r
Drug
concn.
(pg/ml)
(pg/ml)
Group I (control; n 4)
4.0k0.1
S.OkO.2 1.5k0.3
138k1
284+1
780+23
1.8+0.4
-
4.3kO.O
5.3k0.2
I.O&O.l
133&l**
277&2*
906&40*
1.5k0.2
V,: O.OI9+0.003
Group 3 (V, antagonist; n=6)
4.4*1.0**
5.6k0.2
1.1 +0.2
132+1**
272+2**
375+7**
3.4k0.9
V:, 0.007~0.004
5.6f0.1
0.9+0.2
130+1**
269fl**
356+10**
5.6fl.4*
V,: 0.016&0.005
V,: 0.006+0.004
Group I. concro1
T
Group 2, V, antagonist
2
E Glomerular rcler~ir/hya~inMis
T i
E Group 3, V, antagonist
0
Serum
Urinary
Plasma
osmolality osmolality vasopressin
(mosmol/kg) (mosmol/kg) concn.
Group 2 (V, antagonist: n=7)
Group 4
(V, and V, antagonists; n=6) 4.5+1.0**
18
Serum
Serum
creatinine sodium
concn.
concn.
(mg/dl)
(mmol/l)
4
6
Time (weeks)
8
10
Group I
0 Tubulointentitial change
E Arteno/olMclerosir
Group 2
Group 3
Group 4
Fig. 4. Changes in urinary sodium excretion over 10 weeks. The rats
of all groups showed a large increase in sodium excretion from week 6. The
sodium excretion observed in group 3 and 4 rats treated with V, antagonist
with or without V, antagonist was slightly higher than the control group at
weeks 6, 8 and 10, but this did not achieve statistical significance.
Fig. 5. Histopathological score at week 10. Glomerular sclerosir/hyalinosis, tubulointentitial change and arterio/olosclerosis were observed in
the control group. Otherwise, histopathological alterations were significantly ameliorated in group 4 rats treated with V, and V, antagonists, but
not in groups 2 and 3, which were administered V, or V, antagonist alone.
Statistical significance: *P<0.05, **P <O.OI compared with the control
group.
this animal model, the V, antagonist lowered systolic blood pressure, presumably owing to the direct
arterial dilatation [23, 241. However, localized
effects of vasopressin in the kidney could also have
participated, since glomerular mesangial cells possess V, receptors [27] and vasopressin stimulates
mesengial cells to proliferate and to produce protein
in vitro [28]. Therefore, attenuation of the glomerular histopathological alterations (Fig. 5) might be
partially due to inhibition of the direct cellular
effects of vasopressin by V, antagonists. Several
authors [29-311 have proposed a role for angiotensin I1 in the pathogenesis of intraglomerular
hypertension in a renal ablation model. However, in
the present study, since angiotensin levels are likely
to be minimal because of the suppressed reninangiotensin-aldosterone system in DOCA-salt
hypertension [131, it is possible that vasopressin
could raise glomerular hydraulic pressure by selective contraction of the postglomerular efferent arter-
ioles via V, receptors [32]. It is therefore likely that
reversal of glomerular hypertension could be
attained with V, antagonists, which also contributes
to the protection of the glomerulus [30, 33).
A possible involvement of V, agonism in the
progression of renal failure has been proposed
[ 5 , 6, 81. Intraglomerular hypertension could be
induced by antidiuretic hormone [34, 351, presumably due to depression of the tubuloglomerular
feedback system by the V, receptor-mediated urine
concentrating process, i.e. enhanced sodium uptake
in the medullary thick ascending limb of Henle's
loop [ 5 , 3 6 3 8 1 and increased urea concentration in
the thick ascending limb lumen [8], resulting in a
lower salt concentration at the macula densa.
Certainly, the urine concentrating process was inhibited in group 3 and 4 rats by V, antagonists
(Table 1). Thus, V, antagonists could also produce
a decrease in intraglomerular pressure and ameliorate glomerular histopathological alterations. The V,
Vasopressin antagonists and renal failure
403
end-stage renal diseases may play a role in it
[2, 3, 461. The clinical use of vasopressin antagonists has hitherto been restricted [47]. However, the
present study has demonstrated the protective
effects of a combination of V1 and V, antagonists
against the unfavourable effects of vasopressin in the
progression of renal failure in rats, and raises the
possibility of such a combination being applicable
as a therapy for certain types of chronic renal
failure.
ACKNOWLEDGMENTS
We thank Mr S. Kusakari, Mr H. Abe, Mrs A.
Sakamoto and Miss K. Takahashi for their help in
preparing specimens, and Mr K. Takeichi for taking
the photographs.
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