Laboratório de Pesquisa Básica da Disciplina de Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo CEP 05409-003, Brazil
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ABSTRACT |
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The reduction of
urinary volume after the use of thiazide in the treatment of diabetes
insipidus (DI) is known as the "paradoxical effect." Since
enhanced proximal solute and water reabsorption only partially account
for the reduction in urinary volume, an additional diuretic effect on
nephron terminal segments was postulated. Thus the aim of our work was
to investigate the effect of hydrochlorothiazide (HCTZ) on water
transport in the inner medullary collecting duct (IMCD) of normal and
Brattleboro rats. Osmotic water permeability (Pf) and
diffusional water permeability
(Pdw) were
studied at 37°C and pH 7.4 by the in vitro microperfusion
technique. In the absence of antidiuretic hormone (ADH), HCTZ
(106 M) added to the
perfused fluid enhanced
Pf from 6.36 ± 0.56 to 19.08 ± 1.70 µm/s
(P < 0.01) and
Pdw from 38.01 ± 4.52 to 52.26 ± 4.38 ×10
5 cm/s
(P < 0.01) in normal rats and also
stimulated Pf in
Brattleboro rats from 3.53 ± 1.41 to 11.16 ± 1.13 µm/s
(P < 0.01). Prostaglandin E2
(PGE2)
(10
5 M) added to the bath
fluid inhibited HCTZ-stimulated
Pf (in µm/s) as
follows: control, 16.93 ± 2.64; HCTZ, 29.65 ± 5.67;
HCTZ+PGE2, 10.46 ± 1.84 (P < 0.01); recovery, 16.77 ± 4.07. These data indicate that thiazides enhance water absorption in
IMCD from normal rats (in the absence of ADH) and from Brattleboro rats
and that the HCTZ-stimulated
Pf was partially
blocked by PGE2. Thus we may conclude that the effect of thiazide in the treatment of DI occurs not
only in the
Na+-Cl
cotransport in the distal tubule but also in the IMCD.
hydrochlorothiazide; water transport; antidiuretic hormone; prostaglandin E2; diabetes insipidus
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INTRODUCTION |
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AMONG THE MOST WIDELY prescribed drugs in clinical practice, thiazide diuretics are mainstays in the therapy of hypertension and in the management of edema in patients with well-preserved renal function. Thiazides are also currently used in the management of hypercalciuria, nephrolithiasis, and diabetes insipidus (DI).
Three possible mechanisms of NaCl transport in distal segments have
been considered: 1)
Na+-Cl
cotransport, 2)
Na+-K+-2Cl
cotransport, and 3)
Na+-H+
and
Cl
/HCO
3
parallel antiport. At present, it is generally believed that the major
site of action of thiazides is located in the distal convoluted tubule,
as demonstrated in in vivo micropuncture and microperfusion studies
(5-7). Constanzo and Windhager (6), Velazquez et al. (33, 34), and
Ellison et al. (12) demonstrated that thiazides act on the
electroneutral Na+-dependent
Cl
transport mechanism to
decrease Cl
and
Na+ reabsorption. Using
metolazone, a thiazide-type diuretic, Tran et al. (31) proposed that in
the
Na+-Cl
cotransport, the binding site for thiazide is on the luminal side of
the transporter protein, sharing the same site with
Cl
. When thiazides occupy
this site, they may be able to block the ion translocating process.
The administration of thiazide diuretics to patients with DI results in a paradoxical antidiuresis (8, 10, 28). In a study on Brattleboro rats with hereditary hypothalamic DI, Walter et al. (35) showed that the antidiuresis that follows acute administration of hydrochlorothiazide (HCTZ) is entirely secondary to the natriuresis and consequent sodium depletion induced by the drug. Shirley et al. (27) showed that the mechanism of sustained antidiuresis during chronic HCTZ administration in DI differs from that of the acute response. They demonstrated that the proximal tubule was able to increase the fractional fluid reabsorption, reducing the fluid delivery to the distal nephron segments, but they proposed that these changes in proximal tubular function only partially account for the decrease in urinary volume and suggested that the rise in papillary osmolality probably occurs as a result of an increase in water absorption at sites beyond the proximal tubule. Earley and Orloff (10) observed that the inhibition of solute reabsorption in the distal segments alone would merely increase urinary osmolality without affecting urinary volume, and for this reason they assumed that there is a direct or an indirect action of thiazide on other segments.
Bachmann et al. (2) concluded that the predominant site of
thiazide-sensitive
Na+-Cl
cotransporter mRNA expression in rabbit distal nephron is the distal
convoluted tubule and that the sites of mRNA expression of
electroneutral Na+ and
Cl
transport are similar in
rabbits, rats, and mice.
Congenital nephrogenic DI (NDI) is characterized by renal tubular resistance to antidiuretic hormone (ADH), resulting in the excretion of an increased volume of diluted urine, a decrease in total body water, and a rise in plasma osmolality.
No definitive therapy for NDI currently exists. Previous reports have indicated that HCTZ in combination with a prostaglandin synthesis inhibitor is an effective therapy (20). In view of the adverse effects of hypokalemia induced by HCTZ, or the renal complications induced by prostaglandin inhibitors, combined treatment with HCTZ and amiloride, the potassium-sparing diuretic, has been used (1, 16).
In an attempt to elucidate the hypothesis presented above and considering that no data are available about the effect of HCTZ on water transport in the final segments, the purpose of the present study was to directly analyze the effect of HCTZ on water permeability in the in vitro microperfused rat inner medullary collecting duct (IMCD). Our results showed that HCTZ enhanced water permeability in the absence of ADH, providing an improvement in water absorption in the last segment of the nephron when used for DI therapy.
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METHODS |
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The isolated IMCD was perfused by previously described techniques (4, 23).
Male Wistar and Brattleboro rats weighing 120-125 g were studied. All animals were maintained on a standard diet and had free access to tap water. Tubules were isolated from a small slice that was immersed in a dish of chilled Ringer-HCO3 buffer, oxygenated, and kept at pH 7.4 by bubbling the solution with 5% CO2-95% O2. The IMCD was dissected without the use of collagenase or other enzymatic agent. After isolation, the segment was transferred to a temperature-regulated chamber (37°C) mounted on the stage of an inverted microscope. The bathing solution used was 298 ± 4 mosmol/kgH2O Ringer-HCO3 of the following composition (in mM): 115.0 NaCl, 25.0 NaHCO3, 10.0 sodium acetate, 5.0 KCl, 1.0 CaCl2, 1.2 MgSO4, 1.2 NaH2PO4, and 5.5 D-glucose. For the hypotonic solution (70.0 mosmol/kgH2O), NaCl (115.0 mM) was withdrawn. FD&C green dye was added to the perfusate as a visual marker.
Net water absorption
(Jv) was
measured with
[14C]inulin dialyzed
immediately before the experiments. The dialyzed isotope was added to
the perfusion solution at a final concentration of 25-100 cpm/nl.
Jv was calculated
as Vi Vo/L,
where Vi is the perfusion rate,
Vo the collecting rate, and
L the length of the tubule studied (tubule length and inner diameter can be measured to within 0.05 mm
with a precalibrated micrometer in one eyepiece of the
inverted microscope used to observe the perfusion).
Vo was directly measured on the
basis of collection time, whereas
Vi was calculated by the rate of
appearance of the impermeant marker
[14C]inulin in the
collection pipette according to the equation
Vi = Vo(Ino/Ini),
where Ino is the counts per minute
of the collected fluid, and Ini is
the counts per minute of the perfusate. Timed tubular samples were
collected for analysis under mineral oil by aspiration into a
calibrated pipette. All measurements were made 60-90 min after
perfusion of a given nephron segment was started. The inner diameter
(ID) of the perfused segments ranged from 25 to 35 µm and the tubular
length (L) from 1.5 to 2.0 mm. The
area (A) was calculated as
ID ·
· L,
and expressed as ×10
4
cm2.
Osmotic water permeability
(Pf) was
determined by measuring net fluid movement in response to an imposed
gradient. Net fluid reabsorption was induced by perfusion with
hypotonic perfusion solution, 80-90
mosmol/kgH2O (40 mM NaCl), and 300 mosmol/kgH2O bathing solution. The
osmolality of the perfusate and bath fluid was measured, and
Pf (µm/s) was
calculated in each experiment by the following equation (9)
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Diffusional permeability
(Pdw) was
determined from the unidirectional flux of tritiated water
(3H2O)
added to the perfusion solution. The
Pdw
(×105 cm/s) value was
calculated using the following expression (26)
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The baths were checked for osmolality and pH with an osmometer (Advanced Instruments) and a pH meter (Iris 7; Tecnow, São Paulo, Brazil), respectively. The bath fluid was changed every 10 min to reduce the effect of evaporation and consequently the increase in osmotic gradient. The bath osmolality did not change significantly during the 10-min period (from 295 ± 1 mosmol/kgH2O at 0 min to 297 ± 2 mosmol/kgH2O at 10 min).
Timed fluid collections were made with a constant-volume constriction pipette that was rinsed four times with 0.5 ml of water; 5 ml of scintillation liquid was then pipetted into the vial (Aquasol universal cocktail; New England Nuclear, Boston, MA). The isotopic concentration was determined with a liquid scintillator spectrometer (Tri-Carb 1600TR; Packard, Downers Grove, IL).
The isotopic materials used were from Amersham International and New England Nuclear. HCTZ was kindly supplied by the Pharmacy Division of the University Hospital, Faculty of Medicine of São Paulo, University of São Paulo. All other drugs were purchased from Sigma Chemical (St. Louis, MO).
Results are expressed as means ± SE. The data for each period are the mean of three to four collections. Statistical analysis was performed using the Student's t-test and ANOVA.
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RESULTS |
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The dose added to the perfusate
(106 M) was chosen because
it was the lowest dose with reproducible results, although others had
used higher doses (10
4 M)
in micropuncture studies (30, 35). Unless otherwise indicated, the
concentration in the perfused fluid was always
10
6 M. HCTZ added to the
bath fluid had no effect. In a pilot study, it was demonstrated that
HCTZ was able to enhance water transport only when applied to the
luminal side. In this investigation, a dose-dependent study was
performed by adding 10
4,
10
5, and
10
6 M of HCTZ to the bath
fluid, and the results were as follows: control, 5.79 ± 1.41;
10
6 M, 5.65 ± 0.99;
10
5 M, 6.08 ± 071; and
10
4 M, 7.06 ± 0.42.
The effect of HCTZ on water transport is presented in Table
1. In this group of IMCDs, we measured the
effect of 106 M HCTZ on the
Pf of normal rats
in the absence of ADH. HCTZ increased Jv from 1.90 ± 0.57 to 3.11 ± 0.73 nl · min
1 · mm
1
(P < 0.05), which represents an
increase in Pf
from 6.36 ± 0.56 to 19.08 ± 1.70 µm/s (P < 0.01). The reversibility of the action of HCTZ was observed
during the recovery period, when
Pf decreased to
5.93 ± 1.41 µm/s (P < 0.01)
after HCTZ withdrawal.
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In a second group of IMCDs (Table 1), we examined the effect of HCTZ
(106 M) on
Pdw. HCTZ
increased Pdw
from 38.01 ± 4.52 to 52.26 ± 4.38 × 10
5 cm/s
(P < 0.01) with a return to initial
values (37.73 ± 6.22 × 10
5 cm/s) during the
recovery period in the absence of HCTZ.
We tested the effect of HCTZ in Brattleboro rats to avoid possible effects of endogenous ADH. HCTZ increased Pf from 3.53 ± 1.41 to 11.16 ± 1.13 µm/s (P < 0.01), and Pf returned to initial values in the absence of HCTZ (4.24 ± 0.99 µm/s) (P < 0.01) (Table 1).
In the fourth group we examined the effect of prostaglandin
(PGE2).
PGE2
(105 M) was tested to
understand the practice of the use of indomethacin, a PG inhibitor, as
an adjuvant of HCTZ in DI therapy. The results presented in Table
2 show that
PGE2 added to the bath fluid
inhibited the HCTZ-stimulated
Pf from 29.65 ± 5.67 (P < 0.02) to 10.46 ± 1.84 (P < 0.01), with a recovery to
16.77 ± 4.07 µm/s.
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In a final, group we decided to investigate whether the effect of the
HCTZ would be due to its action on
Na+-Cl
cotransport. We performed an experiment using
10
4 M ouabain, added to the
bath. The results presented in Table 2 showed that ouabain
did not block the action of HCTZ (control, 7.35 ± 3.25; HCTZ,
23.17 ± 7.49; HCTZ+ouabain, 25.15 ± 5.37; and HCTZ,
21.34 ± 4.24 µm/s).
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DISCUSSION |
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Despite the widespread use of the thiazides in clinical practice for many years, their sites of action and their effects on collecting duct function have not been fully assessed.
At present, it is generally believed that the major site of action of thiazides is the distal convoluted tubule. This notion is based on data derived from both osmolar clearance and micropuncture studies. The observation that thiazides inhibit free water clearance without affecting free water reabsorption (11, 25, 29) supports the view that these drugs inhibit solute transport in the cortical diluting segments. More direct evidence with regard to the site of action of thiazides has been provided by micropuncture studies (6, 12, 17, 30, 31, 33).
The present in vitro microperfusion study was designed to determine
whether HCTZ has any effect on water transport in the rat IMCD. The
results showed that HCTZ, in the absence of ADH (Table 1, Fig.
1A),
was able to enhance water transport measured both in terms of osmotic
and diffusional permeability. The data from the diffusional
permeability, showing an increase in water conductance in absence of an
osmotic gradient, provide acceptable evidence that the effective
epithelial permeability was changed.
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However, results were obtained only when the diuretic was applied to
the lumen of the tubule and not just added to the bath fluid. It is
well known that HCTZ, which is a sulfonamide compound, is an organic
acid and consequently is secreted into the proximal tubule by the
organic acid secretory pathway, reaching the tubular lumen of the
distal segment where its principal target, the
Na+-Cl
cotransport, is located. Since the vasopressin receptor is located on
the basolateral side of the IMCD cell and since HCTZ works only in the
lumen, our data lead us to hypothesize that thiazide did not act on the
vasopressin receptor to enhance water transport, but required entering
the cells through the luminal membrane, reaching intracellular
structures, and then performing its action. Although our data are
convincing, this hypothesis requires further investigation.
To assure the absence of endogenous ADH, all experimental measurements were performed ~60 min after the rats were killed, with the sampling procedure beginning after an equilibration period of 30-45 min. Another alternative to rule out possible effects of endogenous ADH was to use rats with DI (Brattleboro strain), which cannot elaborate ADH (32). The data from these experiments confirmed what was demonstrated for normal rats, i.e., HCTZ enhanced water absorption also in Brattleboro rats (Fig. 1A).
According to studies reported by Earley and Orloff (10) and Skadhauge (28), the administration of thiazide diuretics to patients with DI results in a paradoxical antidiuresis. This antidiuresis is not well understood, but Walter et al. (35) tried to explain this phenomenon using micropuncture techniques applied to Brattleboro rats. They demonstrated that acute HCTZ administration produced a marked antidiuresis due to a rise in fractional fluid reabsorption by proximal tubules, diminishing distal delivery and restricting urinary flow. In a long-term HCTZ treatment, Shirley et al. (27) proposed that "the changes in proximal tubular function during chronic thiazide treatment only partially account for the reduction in urine volume; it seems probable that the raised papillary osmolality, by enhancing water reabsorption at sites beyond the proximal tubule, makes a greater contribution to antidiuresis." On this basis, our data confirm a direct action of this diuretic on the last segment of the nephron from both normal ADH-depleted rats and Brattleboro rats.
PGE2 was directly used to try to understand why indomethacin is used as a coadjuvant in DI therapy. Indeed, PGE2 is known to be a blocker of vasopressin-adenylate cyclase stimulation when it participates in the loop of the "negative feedback" in the vasopressin cascade (22). Our results showed that PGE2 decreased the effect of HCTZ when added after HCTZ, i.e., PGE2 produced a rapid blockade in the HCTZ-stimulated Pf. Thus these results inform us that when indomethacin was administered with HCTZ, it can enhance the action of this diuretic, providing evidence as to why this association is effective in DI treatment.
During the PGE2 period (Table 2),
in the absence of ADH and HCTZ,
PGE2 drastically reduced
Pf, in contrast
to the data reported by Nadler et al. (21) and Hébert et al.
(15). The present experiments and other in vitro studies from our
laboratory (18, 19) showed that under basal conditions, and in the
presence of ADH, 105 M
PGE2 always inhibits
Pf rapidly and
reversibly, confirming the well-known
PGE2 blocker effect. This
PGE2 effect on HCTZ-stimulated Pf may explain
why indomethacin is sometimes used as a thiazide coadjuvant in the
treatment of NDI (13). HCTZ (1-2
mg · kg
1 · day
1)
and indomethacin (0.75 to 1.5 mg/kg) used with a low osmolarity and
low-sodium diet substantially reduced water excretion (1, 3).
Although the effect of thiazide has been described in the distal
convoluted tubule, we cannot rule out the possibility that HCTZ
enhances water transport by its effect on
Na+-Cl
cotransport in IMCD. To study this possibility, it would be necessary to inhibit this cotransport, but it is well known that all substances that block this cotransport are thiazides and thiazide-like diuretics and that these drugs act by the same mechanism, i.e., using the same
chemical radical operating at the same binding sites of the Na+-Cl
cotransporter (14). On this basis, it would not be correct to use a
thiazide diuretic to study this. The only way to try to
overcome this problem was to use a strategy to indirectly reduce the
action of this
Na+-Cl
cotransporter by blocking
Na+-K+-ATPase
with ouabain. With the reduction of the
Na+ gradient between the
intracellular and the luminal fluid, the Na+-Cl
symport would then decrease. Rocha and Kudo (24) showed that ouabain
(10
4 M) reduced the
Na+ lumen-to-bath flux in IMCD,
demonstrating that the entry of
Na+ through luminal membranes is
directly or indirectly coupled to Na+-K+-ATPase.
Our data showed that the effect of HCTZ was not abolished in the
presence of this glycoside, leading us to suppose that the HCTZ effect
on water absorption is not linked to the performance of the NaCl
cotransporter. A possible effect produced by the carbonic anhydrase-inhibiting capability of HCTZ was not considered, because this capability is very low (14).
Finally, the present results provide some additional information about the effect of HCTZ on IMCD. Although this effect was shown in an in vitro study, we believe that it could be extended to human beings and, when evaluated in general, explain the capacity of HCTZ to enhance water absorption in a patient with DI. The data showing the blocker effect of PGE2, together with the absence of an effect on the basolateral side, may shed some light on a possible mechanism of action of HCTZ, i.e., the above-mentioned idea, that HCTZ must enter the cell to produce its effect and a possible action may be to stimulate structures of the vasopressin cascade inside the cell, finishing with the enhancement of the water permeability. This hypothesis requires confirmation, through studies designed to clarify the mechanism by which the thiazide acts.
We are not aware of any other study in which the effect of HCTZ on water transport was measured in IMCD.
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ACKNOWLEDGEMENTS |
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We thank Elettra Greene for revising the English text.
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FOOTNOTES |
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This work was supported by LIM HC/FMUSP and by Fundaçao de Amparo à Pesquisa do Estado de São Paulo. A. J. Magaldi was supported in part by a fellowship from Conselho Nacional de Pesquisa.
Portions of this work were presented at the XIIth Annual Meeting of the International Congress of Nephrology, Jerusalem, 1992.
Address for reprint requests and other correspondence: A. J. Magaldi, Faculdade de Medicina da USP, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, SP, Brazil (E-mail: biomag{at}usp.br).
Received 14 November 1997; accepted in final form 30 June 1999.
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