V1 receptors in luminal action of vasopressin on
distal K+ secretion
José B. O.
Amorim and
Gerhard
Malnic
Department Physiology and Biophysics, Instituto Ciências
Biomédicas, Universidade de São Paulo, São Paulo
05508-900, Brazil
 |
ABSTRACT |
Luminal perfusion
with collected proximal fluid increases distal K+ secretion
compared with artificial solutions. Arginine vasopressin (AVP), present
in luminal fluid, might be responsible for this observation.
K+ secretion rate (JK) was measured by
K+-sensitive microelectrodes during paired luminal
stationary microperfusion with control and AVP-containing 0.5 mM
K+ solutions. JK was 1.34 ± 0.35 (n = 24 tubules)
nmol · cm
2 · s
1
during perfusion with 10
9 M AVP, against
0.90 ± 0.12 nmol · cm
2 · s
1
(n = 21) in control (P < 0.02). With
10
9 M
AVP+10
6 M
-mercapto-
-
-cyclopenta-methylenepropionyl1,
O-Me-Tyr2-Arg8 vasopressin (MCMV), a specific
peptide V1-receptor antagonist, JK was
0.36 ± 0.067 against 0.77 ± 0.10 (control; n = 9)
nmol · cm
2 · s
1
(P < 0.01). With 10
6 M MCMV
alone, JK was 0.37 ± 0.04 against a control of
0.62 ± 0.06 (n = 19)
nmol · cm
2 · s
1
(P < 0.01). A peptide V2 antagonist had no such
effect. In Brattleboro rats, which do not produce endogenous AVP, MCMV
had no effect when given alone, although AVP still stimulated
JK. In conclusion, luminal AVP stimulates distal
JK significantly. The V1 antagonist MCMV inhibits the effect of AVP but also reduces JK
when given alone. This suggests that AVP acts luminally via
V1 receptors but also that there appears to be a background
effect of endogenous AVP blocked by the antagonist.
potassium; anti-V1; distal tubule; microperfusion
 |
INTRODUCTION |
IT HAS BEEN NOTED THAT DURING free-flow micropuncture
experiments in cortical distal tubules, "in vivo" K+
secretion at a given flow rate is considerably higher than during microperfusion with artificial Ringer solutions (23, 26). It is well
known that distal K+ secretion is a function of flow rate,
distal sodium load, pH. and transepithelial potential difference (PD),
among other factors (14, 43). However, it has also been shown that
during distal perfusion with native proximal fluid collected before the
experiment, distal K+ secretion is markedly higher than
when an artificial Ringer solution of comparable composition is
perfused (27). This finding suggested the presence, in native proximal
fluid, of endocrine or paracrine factors that might stimulate this
transport process by acting at the luminal surface of tubule cells. A
similar suggestion has been made for fluid and sodium reabsorption in
proximal tubule (19).
In the present work, we have investigated the role of arginine
vasopressin (AVP) in distal K+ secretion. AVP is a peptide
hormone that has been found to affect this process and is present in
luminal fluid in physiological conditions (6, 21). Vasopressin has been
shown by several groups to stimulate K+ secretion in
cortical distal tubule (9, 12) and in cortical collecting duct (8, 35,
41) and is found in final urine in significant concentrations (21). ADH
action on K+ secretion has been found mostly in rat
cortical collecting duct, especially when electrolyte transport is
stimulated by mineralocorticoids such as DOCA (35, 40). In addition,
luminal action of AVP on electrolyte transport was observed in rabbit
cortical collecting duct (2, 21).
Most studies have detected AVP action when applied at the basolateral
surface of distal tubules and collecting ducts. This action has been
shown to be mediated mostly by V2 receptors via the
adenylate cyclase/cAMP signaling system (8, 17). However, in recent
years V1 receptors have been detected both in apical and
basolateral membrane domains and have been shown to mediate AVP
activity at the luminal surface of cortical collecting duct via
phospholipase C/inositol 3,4,5-triphosphate (IP3)/calcium signaling (17, 21, 32).
In the present work, we have applied AVP and its antagonists from the
luminal surface of the cortical distal tubule (initial collecting duct)
and measured the rate of K+ secretion by an in vivo
microperfusion technique. The results have shown that AVP
is an important modulator of distal K+ secretion also when
applied from the luminal cell surface in this segment, acting via
V1 receptors.
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METHODS |
Male Wistar rats weighing 180-320 g were anesthetized with
Inactin, 100 mg/kg, and prepared for in vivo micropuncture as described previously (15). Stationary microperfusion experiments were performed
as summarized in Fig. 1. A proximal tubule
was punctured by means of a double-barreled micropipette, one barrel
being used to inject FDC green-colored perfusion solution, and the
other to inject Sudan black-colored castor oil used to block the
injected fluid columns in the lumen. The control solution contained 100 mM NaCl, 20 mM Na HEPES, 0.5 mM KCl, 1 mM CaCl2, and
raffinose (added to minimize fluid reabsorption) to reach an osmolality of 300 mosmol. pH was adjusted to 6.5. A single micropipette containing the same Ringer solution plus the polypeptide agent was impaled into a
neighboring proximal loop or into an early distal loop. A late distal
segment of the same nephron, recognized by the colored perfusion and by
having a transepithelial PD of >20 mV, lumen negative, was impaled by
a double-barreled asymmetric microelectrode, the larger barrel
containing at its tip the K+-sensitive ion-exchange resin
(Fluka, Buchs, Switzerland) and the smaller (reference), 0.24 M NaCl
and 0.76 M Na acetate, colored by FDC green. This K+-free
solution was calculated to have mean similar cation and anion
mobilities, because the mobility in solution of Cl
is larger than that of Na+ and that of acetate, smaller.
The microelectrode had a tip diameter of ~1 µm, and the reference
barrel had a resistance of <5 M
. Additional properties of the
microelectrode were described previously (45). Standards had a
composition of 3, 10, or 30 mM KCl, and 100 mM NaCl was added to each
of these solutions to compensate for the Na+ sensitivity of
the resin. Mean decade voltage difference for K+ was 42.8 ± 0.51 (n = 132) mV. The electrodes were calibrated before
and after every impalement by superfusion of the kidney surface with
standards at 37°C. A luminal oil block was split by perfusions
performed by hand-held, air-filled syringes connected to the
micropipette holders by polyethylene tubing, applying pressure to the
solutions in the micropipettes. Perfusion rate was considered adequate
when the color of the perfused segment was that of the perfusion
solution, the segment was only moderately expanded, and the perfusion
rate was sufficient to lower luminal K+ concentrations to
values near those of the perfusion fluid, i.e., 0.5 mM. After the
concentration reached this level, perfusion was stopped and an
additional oil block was introduced into the tubule lumen, and the
increase in luminal K+ activities, representing
K+ secretion, followed until a stable level was reached.

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Fig. 1.
Schematic drawing of experimental system. Left: double-barreled
perfusion pipette with perfusion solution (P) and castor oil (C).
Right: double-barreled microelectrode with
K+-sensitive ion-exchange resin (IE) and reference solution
(Ref). An additional single-barreled micropipette (S) is used in
proximal or early distal tubule for experimental solution. This figure
is modified from Ref. 11.
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Every tubule was perfused first with control solution, and then with
the active agent, allowing for paired measurement of K+
secretion. By this technique several (~2-5 each) control,
experimental, and recovery curves were obtained, the mean of control
plus last recovery curves and experimental curves constituting the pair of values for this tubule. The value of n given for an
experimental condition corresponds to the number of perfused tubules,
approximately one to three being perfused in one rat. Statistical
evaluation was performed by the paired t-test, comparing the
means of control and experimental values of every tubule. As seen in
Fig. 2, luminal K+ activity
fell to 0.5 mM initially and then recovered progressively to a
stationary level (K+s). The voltage
between the microelectrode barrels, representing the luminal
K+ activity, was sampled every second by an analog-digital
converter (Lynx, Sao Paulo, Brazil) in a microcomputer (model 333D,
Dell). At the same time, the PD between the reference barrel and ground (the rat tail) was recorded, giving the evolution of transepithelial PD
with time during the perfusion (see Fig. 2). The data were analyzed by
a Visual Basic program by Excel software, fitting an exponential to the
approach of K+ activities to their stationary level by
plotting the differences between luminal K+ activity and
K+s against time, as given in Fig. 3. The half-time (t1/2)
of the approach of K+ activities to their stationary level
was calculated from this exponential. Secretory K+ fluxes
(JK) were obtained by the following relationship
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where
t1/2 is the half-time of K+ activity
increase, K+s is the stationary
K+ activity, K+o is the
initial K+ activity (taken as 0.5 mM), and r is the
tubule radius (45), a relationship we have used before for the
measurement of bicarbonate reabsorption (11).

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Fig. 2.
Record of experiment measuring K+ activity (A) and
transepithelial potential difference (Vt; B) in
renal distal tubule of rat. Note that during perfusion with 0.5 mM
K+ solution ( , P) there is a marked reduction of both PD
and K+ activity, which both return to control levels with
time after blocking of perfusion solution with oil in lumen ( , B).
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Fig. 3.
Difference in K+ concentration
( [K+]; in mM) against time (s) during
control and 10 11 M arginine vasopressin
(AVP) perfusion of cortical distal tubule, after perfusion with 0.5 mM
[K+] and blocking with oil. Difference refers
to [K+] in stationary condition minus
[K+] at time t. Continuous curve is
calculated variation of [K+] with time,
assuming exponential approach of these differences to stationary
[K+] level.
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Vasopressin, the V1-receptor antagonist
(anti-V1;
-mercapto-
-
-cyclopenta-methylenepropionyl1,
O-Me-Tyr2-Arg8 vasopressin; MCMV), and the
V2-receptor antagonist (anti-V2; adamantaneacetyl1,
O-Et-D-Tyr2, Val4
aminobutyryl6, Arg8,9 vasopressin; AAV)
(28) were obtained from Sigma Chemical (St. Louis, MO). Benzamil
(benzylamiloride hydrochloride) was obtained from Research Biochemicals
(Natick, MA). Other chemical products were of analytic grade.
Statistical comparisons were made by the paired t-test, or,
when nonpaired groups were compared, by ANOVA followed by the Bonferroni contrast test. The probability of 0.05 (5%) was taken as
the limit of significance.
 |
RESULTS |
The basic experiment of this series involves injecting a low (0.5 mM)-K+ solution into the tubule lumen and following the
changes of this concentration back to its stationary level after the
fluid column is blocked in the lumen (Fig. 2). This procedure allows
for the construction of graphs such as that in Fig. 3, which gives the evolution of the difference between the stationary K+
concentration and the concentration at time t, which decays
exponentially toward zero. The data are obtained by digitization of the
measurements performed by means of the potassium microelectrode, which
are then transferred to an Excel chart and processed by a "macro" within this software. Figure 3 compares data obtained during perfusion with control Ringer solution, that is, a perfusion in the absence of
any active agent, with data obtained during perfusion with solution to
which 10
11 M AVP was added. Figure
4 shows a sequence of perfusions in
one distal tubule to which 10
11 M AVP
was applied. It is clear that during luminal perfusion with AVP a
consistent rise in JK is obtained. Such a sequence gives rise to one pair of data points in all our tables or figures, control and experimental. The control value includes the
mean of the points before application of AVP plus those corresponding to recovery of control levels after AVP, and the experimental value
includes the points during AVP perfusion.

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Fig. 4.
K+ secretion rates (JK) measured during
sequence of perfusions in a distal tubule in control conditions and
during perfusion with 10 11 M AVP.
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To study the effect of conditions that are known to modify
K+ transport in distal tubule, luminal perfusions with
benzamil, an amiloride analog with almost only Na+-channel
blocking activity and no effect on Na+/H+
exchange (24), and with Ba2+, a K+ channel
blocker, were performed. Table 1 gives mean
K+s values measured during perfusion,
when luminal K+ levels returned to their stationary level,
t1/2, half-times of the approach of luminal
K+ concentrations to their stationary level, and
transepithelial PD and JK in control conditions and
after perfusion with 10
4 M benzamil;
n is the number of perfused tubules. K+
concentrations are markedly reduced in this condition, and
t1/2 is significantly higher than control
values, indicating that the influx of K+ is impaired by
this agent. In addition, it is noted that the mean
JK falls markedly; as expected, transepithelial PD
falls to near zero in this condition. Table
2 shows experiments in which K+
channels are blocked by luminal perfusion with 3 mM Ba2+
with and without addition of AVP 10
11 M. It is clear that perfusion with Ba+2 reduces K+
secretion markedly, with reduction of stationary K+
concentration ([K+]s)and increase
in t1/2. Transepithelial PD is moderately
increased, as expected. However, when a comparison is made with PD
measured immediately after perfusion was started , a value of 38.3 ± 3.5 (n = 17) mV was obtained in a control group, against 56.8 ± 4.0 (n = 21) mV in tubules perfused with 3 mmol/l
Ba+2, a significant difference compatible with the expected
decrease in luminal K+ conductance.
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Table 1.
Stationary K+ concentration, half-time of
K+ equilibration, transepithelial potential
difference, and K+ secretion rate in cortical
distal tubules of rats during perfusion with 10 4 M
benzamil
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Table 3 shows a summary of
[K+]s and t1/2
data during AVP action on distal K+ secretion, giving the
mean control data compared with the mean experimental values; n
represents the number of perfused tubules. In most experiments
[K+]s levels are not significantly
altered, whereas t1/2 are significantly shortened
when AVP is perfused and increased in the presence of the
anti-V1 receptor agent. Figure
5 shows JK (in
nmol · cm
2 · s
1)
at different luminal AVP concentrations. Figure
6 gives the effect of the
anti-V1 receptor peptide MCMV, alone and in combination with AVP, on JK, and Fig.
7, the effect of the anti-V2
receptor peptide AAV. It is noted that
10
11 and
10
9 M AVP stimulate K+
secretion significantly, which is an important finding because physiological plasma levels of AVP are in the range of
10
12 to
10
11 M, and final urine AVP levels are
up to 1,000 times higher than plasma levels (29). AVP at
10
6 M shows some stimulation, but
without reaching significance. The addition of anti-V1
10
6 M to
10
11 M AVP reverts the action of AVP and
in addition reduces K+ secretion significantly below
control, but anti-V1 alone has the same effect. On the
other hand, the V2-receptor antagonist, anti-V2
(see METHODS) has no significant effect when given alone and does not abolish the action of AVP when given together with this
peptide. These data indicate that the effect of AVP observed during
luminal perfusion of the peptide is mediated by V1-type receptors and that, even in the absence of this agent, the perfusion with anti-V1 reduces distal K+ secretion,
suggesting background activity of the hormone in distal tubule. In
addition, data in Table 2 indicate that AVP+Ba2+ in the
lumen does not increase K+ secretion significantly,
suggesting that AVP might act by affecting luminal K+
channels.
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Table 3.
[K+]s values and equilibration
t1/2 in cortical distal tubule perfused with AVP and
anti-V1 and V2 receptor agents
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Fig. 5.
Distal JK: effect of luminal perfusion with AVP at
different concentrations [10 11
(A), 10 9 (B), and
10 6 M (C)].
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Fig. 6.
Distal JK: effect of luminal perfusion with AVP
(A) and with V1-receptor antagonist
(AV1)
-mercapto- - -cyclopenta-methylenepropionyl1,
O-Me-Tyr2-Arg8 vasopressin (MCMV; B and
C). See METHODS.
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Fig. 7.
Distal JK: effect of luminal perfusion with AVP
(A) and with V2-receptor antagonist
(AV2) adamantaneacetyl1,
O-Et-D-Tyr2, Val4
aminobutyryl6, Arg8,9 vasopressin (AAV;
B and C).
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Table 4 gives mean transepithelial PD in
control and AVP perfused distal tubules. Although there was a tendency
of PD to decrease during the experimental period in some of the groups, differences between control and experimental groups were not
statistically significant, which is compatible with the absence of
differences in [K+]s in most
groups.
The activity of the V1-receptor antagonist
(AV1) alone could be due to an unspecific action of this
substance, that is, to an action not related to the blocking of
V1 receptors for AVP. To study this possibility, we used
homozygous Brattleboro rats, which do not produce AVP but do have
receptors for the hormone (34). Results obtained in these rats are
given in Table 5 and in Fig.
8. It is clear that in these rats
K+ secretion is significantly stimulated by
10
11 M AVP and that AV1
abolishes the stimulatory action of AVP but, when perfused alone, does
not inhibit potassium secretion, as had been found in control rats;
this supports the view that this effect might be due to the presence of
a basal level of AVP in the control group, which is absent in the
Brattleboro strain. In these rats, distal transepithelial PD was not
significantly different in the groups that were investigated, being on
the order of 40-50 mV.
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Table 5.
[K+]s values and equilibration
t1/2 in distal tubules of Brattleboro rats, perfused with
AVP and anti-V1 receptor agent
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Fig. 8.
Distal JK in Brattleboro rats: effect of luminal
perfusion with AVP (A) and with V1-receptor
antagonist MCMV (B and C).
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 |
DISCUSSION |
The use of stationary microperfusion to study distal K+
secretion is a methodological innovation. This method has been used before for the analysis of H+ secretion and bicarbonate
reabsorption in nephron segments (11, 15) and for the determination of
proximal tubule K+ transport (45). It allows for paired
determinations of ion transport, that is, for comparison of control and
experimental perfusions in the same tubule, while luminal
K+ activities in the perfused segment is measured. In
addition, the studied segment is punctured only with a thin
microelectrode (tip diameter ~1 µm), because perfusion can be made
at a distance from the measurement site. The technique was validated by
studying the effect of some factors known to affect K+
secretion. Thus luminal perfusion in the presence of 3 mM barium reduced JK to 22% of control (see Table 2). This
finding indicates that blocking of luminal K+ channels
probably abolishes cellular K+ secretion, which is
responsible for 78% of distal K+ secretion, whereas the
remainder probably represents K+ transport via the
paracellular path along a favorable electrical potential gradient.
Similar observations were made in the rabbit cortical collecting duct
(30). This finding also suggests that K+ secretion by KCl
cotransport is only a minor component of this process and that AVP
stimulation does not involve this pathway (see Table 2) (10). In
addition, reduction of transepithelial PD by a specific blocker of
apical Na+ channels, benzamil (See Table 1), which
depolarizes PD, also causes a marked reduction of distal K+
secretion (24), as expected from the electrical PD of this transport
(13).
Stimulation of electrolyte, including K+, transport
by vasopressin has been observed in several renal
epithelia. Increase in K+ secretion was detected during
parenteral vasopressin administration in distal tubule perfusions (12),
and luminal application of the hormone to the cortical collecting duct
activated luminal chloride conductance (2, 5, 31). We are showing here
that in late distal tubule, corresponding to the initial collecting duct, this hormone is active in K+ transport when applied
to the luminal cell surface. In addition, the action of the hormone is
abolished by apical anti-V1
(10
6 M) but not by anti-V2
(10
6 M) receptor blockers.
V1 receptors have been localized by immunostaining in
distal tubule connecting segment and in cortical collecting duct at both apical and basolateral membrane (16). V1a receptor
mRNA has been detected by PCR in rat initial cortical collecting duct (the micropuncturer's late distal tubule) (39). In addition, AVP has
been shown to act also via oxytocin receptors (38); phospholipase
C-coupled V1-type non-V1a and
non-V1b receptors, leading to an increase in cell calcium,
have also been suggested to mediate AVP action in inner medullary
collecting duct cells (25). The V1 antagonist used in the
present work acts unspecifically on the different V1
subtypes that have been described, not allowing for distinction between
them. However, the V1 receptor described by most
investigators for the cortical collecting duct is the V1a
subtype (1, 25, 39).
Previous data from our laboratory have shown that luminal AVP acts on
H+ secretion in both early and late distal tubule,
stimulating this process at 10
9 M (3).
Evidence was obtained that AVP stimulates the
Na+/H+ exchanger of the apical membrane of this
segment. In addition, it was found that a V1 antagonist
(the same used in the present experiments) abolished the AVP effect,
whereas a V2 antagonist had no effect. In a comparison of
these data to the present findings, it may be suggested that the
regulation of H+ secretion via the
Na+/H+ exchanger shares a common mechanism with
that of K+ secretion in this segment.
The study of AVP antagonists gives important information about the
signaling pathways that may be involved in the regulation of distal
tubule K+ secretion. It is well known that V2
receptors are present mostly at the basolateral membrane, where they
mediate the hydrosmotic effect of AVP at picomolar concentrations. This
mechanism is known to involve the adenylatecyclase-cAMP-protein kinase
A pathway (4, 8). On the other hand, V1 receptors mediate
AVP action mostly via a Gq-11 protein-phospholipase
C-IP3-protein kinase C-Ca2+ pathway.
Evidence for this path was described for rabbit proximal tubule (46),
rat thick ascending limb (6, 36), and rabbit cortical collecting duct
principal cells (7, 21). The impairment of AVP action by an
anti-V1-receptor antagonist and the absence of a similar
effect by a V2-receptor antagonist suggests that the
signaling pathway involving protein kinase C and/or cell
Ca2+ might be decisive for luminal action of AVP on
K+ secretion.
Data obtained by the patch-clamp technique have brought important
information about the mechanism by which AVP may affect K+
transport. It was shown that the addition of AVP to the bath medium of
split-open cortical collecting ducts induced the activity of previously
silent apical channels in the cell-attached configuration; that is, AVP
induced a larger number of low-conductance K+ channels to
function, increasing apical membrane conductance of principal cells
(8). These authors also obtained evidence that this mechanism was
mediated by the cAMP-protein kinase A pathway. On the other hand, in
chick kidney cells in primary culture Ca2+-activated
K+ channels have been found on the apical membrane, and it
was shown that these channels increased their open probability when AVP was added to the medium in the cell-attached condition. These are
107-pS channels, and it is possible that they might mediate a
Ca2+-dependent effect of apical membrane K+
conductance (18). It has also been proposed that this channel might be
responsible for regulatory volume decrease, as would occur after cell
swelling due to inhibition of the Na+/K+ pump,
(37) but possibly also for stimulation of sodium entry into principal
cells of the collecting duct by vasopressin (2, 33). More recently, an
additional type of Ca2+-dependent, voltage-independent
small K+ channel has been described; it has been found in a
large number of tissues, and its properties are compatible with those
described in the present paper (22, 44).
Besides AVP action on luminal channels, an indirect mechanism for
activation of luminal K+ secretion has been proposed:
luminal AVP, increasing cytosolic Ca2+ levels, could
inhibit basolateral intermediate conductance (~150 pS) channels,
impairing basolateral K+ recirculation and thereby
increasing cell K+, and thus increasing the luminal
gradient driving this ion's secretion (20). These considerations
suggest that AVP action on distal K+ secretion might be
mediated by increases in cytosolic Ca2+. Of course, more
detailed studies will be necessary to define the K+ channel
and signaling pathway responsible for the described action of AVP.
An interesting finding was the observed inhibition of K+
secretion by perfusion with the anti-V1-receptor antagonist
alone. This could be due to an unspecific inhibitory action of this
peptide but might also indicate that in control conditions there may
exist a basal level of AVP binding to luminal V1 receptors,
causing some tonic activation of K+ secretion. Inhibitory
actions of this nature have not been reported before. However,
perfusion of rat inner medullary collecting ducts with
anti-V1a receptor agents showed a moderate reduction of
cell Ca2+ levels, which might impair a cellular
Ca2+-dependent mechanism (25). To eliminate the possibility
of an unspecific inhibitor effect of the anti-V1 agent used
in our experiments, we performed similar experiments in homozygous
Brattleboro rats, which are known to be devoid of endogenous AVP
production (42). In these rats, perfusion with exogenous AVP stimulated
distal K+ secretion, showing the presence of receptors for
this peptide. Although their distal control JK
values were not much lower than those found in Wistar rats, the
anti-V1 agent had no significant effect, showing that this
peptide had no AVP-independent action. An additional question involves
the duration of AVP binding to V1 receptors in distal
tubule apical membranes. Figure 4 indicates that AVP washout (perfusion
with control solution after AVP-containing solution) in our experiments
is not immediate but takes several minutes to approach preperfusion
levels, suggesting that the maintenance of residual levels of AVP
binding in control conditions might be expected. These findings support
the view that in control Wistar rats a portion of the normally observed
rate of distal K+ secretion may be dependent on endogenous
AVP levels.
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ACKNOWLEDGEMENTS |
The authors thank Drs. Margarida de Mello Aires, Guillermo
Whittembury and Antonio C. Cassola for suggestions and review of the manuscript.
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FOOTNOTES |
This work was supported by the Fundação de Amparo à
Pesquisa do Estado de São Paulo and Conselho Nacional de
Desenvolvimento Cientifico e Tecnológico. J. B. O. Amorim was
supported by a fellowship from the Fundação
Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior (Brazilian Ministry of Education).
Present address of J. B. O. Amorim: Basic Science Dept., Faculdade de
Odontologia de São José dos Campos UNESP, São Paulo, Brazil.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Malnic,
Depto. Fisiologia e Biofísica, Inst. Ciências
Biomédicas USP, Av. Prof. Lineu Prestes 1524, 05508-900
São Paulo, Brazil (E-mail: gemalnic{at}usp.br).
Received 29 April 1999; accepted in final form 19 January 2000.
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