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1
/ mice
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198-4575
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Large-conductance
Ca2+-activated K+ channels (BKCa)
are composed of pore-forming 
-subunits and one of four accessory
-subunits. The 1-subunit, found predominantly in smooth muscle,
modulates the Ca2+ sensitivity and pharmacological
properties of BKCa. BKCa-1 null mice
(M1
/) are moderately hypertensive, consistent with
the role of BKCa in modulating intrinsic vascular tone.
Because BKCa are present in various renal cells including
the mesangium and cortical collecting ducts, we determined whether
fluid or electrolyte excretion was impaired in M1/
under euvolemic, volume-expanded, or high-salt diet conditions. Under
euvolemic conditions, no differences in renal function were found
between M1/ and M1+/+. However,
glomerular filtration rate (GFR) and fractional K+
excretion were significantly impaired in M1/ in
response to acute volume expansion. In contrast, M1/
exhibited enhanced Na+ excretion and fractional
Na+ excretion responses to acute volume expansion.
Differences in renal function between M1+/+ and
M1/ were not observed when chronically treated with
a high-salt diet. These observations indicate that the 1-subunit of
BKCa contributes to the increased GFR that accompanies an
acute salt and volume load and raises the possibility that it is also
involved in regulating K+ excretion under these conditions.
large-conductance, calcium-activated potassium channels; maxi K channel; glomerular filtration rate; volume expansion; potassium excretion
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LARGE-CONDUCTANCE,
CA2+-ACTIVATED potassium channels
(BKCa) are composed of both pore-forming - and accessory
-subunits. At least four distinct -subunits, each with a
tissue-specific distribution, have been described. When the
1-subunit, found primarily in smooth muscle cells, is expressed with
the -subunit, the voltage and calcium sensitivities of
BKCa are enhanced (2). Conversely, BKCa in cerebral artery myocytes from 1 knockout mice
(M1/) have a reduced open probability at a given
voltage and Ca2+ concentration (2). In
addition, these mice also have deficient regulation of tone in visceral
smooth muscle, such as in the urinary bladder (23). In
vascular smooth muscle, a lack of the 1-subunit and the resulting
low open probability of BKCa may cause a reduced hyperpolarizing feedback response to contractile agents, resulting in
greater vascular tone and generalized hypertension (16). Indeed, the mean arterial pressure (MAP) in M1/ of
the C57BL/6 strain is elevated by ~20 mmHg (2).
Whereas hypertension can originate from elevated intrinsic vascular
tone, MAP is regulated by multiple complex mechanisms that include
baroreceptor and renal feedback reflexes, such as pressure-natriuresis
and renin release. Indeed, polymorphisms in the human
BKCa-1 have been shown to correlate with baroreflex and
arterial pressure regulation (7).
BKCa have been reported in several renal cells, including
mesangial cells as well as epithelial cells of the cortical collecting duct (11), proximal tubule (10), and thick
ascending limb (20). However, the function of
BKCa in these cells in relation to whole animal electrolyte
balance has not been determined. In this study, we designed experiments
to determine the significance of the 1-subunit with respect to fluid
and electrolyte balance. Although the open probability of
BKCa is very low under basal conditions, these channels are
important mediators of compensatory hyperpolarizing responses after
agonist stimulation. Therefore, we examined M1/
under both euvolemic and volume-expanded conditions, in which a variety
of possible influences including increased circulating atrial
natriuretic peptide (ANP), stretch, intracellular Ca2+, and
increased flow of plasma and filtrate could demand proper function of
the renal BKCa.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All experiments were performed under the guidelines of the
Institutional Animal Care and Use Committee of the University of Nebraska Medical Center. This study utilized M1/
mice (with a homogeneous C57BL/6 background) generated by Brenner et
al. (2) and C57BL/6 control mice (M1+/+) of
both sexes, which were approximately 3 mo of age. Mice received standard chow containing 0.4% NaCl and water ad libitum. Some mice
received a high-salt (8% NaCl) diet for 2-3 wk before surgery.
Surgical procedures.
Surgical and clearance procedures were performed as previously
described by Wang et al. (30). In brief, mice were
anesthetized with Inactin [0.14 mg/g body wt (BW)] and kept at a body
temperature near 36°C, using a heat lamp. As required, additional
doses of Inactin were used to maintain anesthesia. A tracheostomy was
performed using polyethylene (PE)-50 tubing, and the end of the
tracheal cannula was exposed to a stream of oxygen-rich air. The left
external jugular vein was cannulated with PE-10 tubing for the infusion of fluids, and the bladder was cannulated with PE-50 tubing for urine
collection. The right common carotid artery was cannulated with PE-10
tubing for arterial pressure measurements and blood sampling. Arterial
pressure was monitored continually and recorded at 5-min intervals.
Urine was collected and stored under mineral oil. Physiological saline
solution (PSS) containing (in mM) 135 NaCl, 5.0 KCl, 2.0 MgCl2, 1.0 CaCl2, and 10 HEPES as well as 10 µg/ml FITC-inulin was infused at a rate of either 0.4 (euvolemic) or
2.0 ml · h1 · 25 g BW1 (volume expanded). Because FITC-inulin is light
sensitive, all syringes, tubing, and collection vials were protected
from light. The length of the equilibration period was 2 h for the
euvolemic treatment and 1 h for the volume-expansion treatment.
After an equilibration period, a blood sample (~20 µl) was taken
and urine was collected for a 30-min period. At the end of the period,
a larger plasma sample was taken for measurements of plasma
Na+ ([Na+]), K+
([K+]), and inulin concentrations ([inulin]). Urinary
volume was determined gravimetrically, and the [inulin] of the two
plasma samples was averaged for calculation of the glomerular
filtration rate (GFR).
Measurements of [Na+],
[K+], and [FITC-inulin] in urine and
plasma.
After the completion of an experiment, urine and plasma samples were
stored in the dark at 
70°C. [Na+] and
[K+] in urine and plasma were measured using an
Instrumentation Laboratory 443 Flame Photometer. Plasma samples were
run in duplicate. Within 1 wk of the experiment, [FITC-inulin] was
measured using a fluorescent microplate reader (Cary Eclipse
Fluorescence Spectrophotometer, Varian) as described by Lorenz and
Gruenstein (17-19). For each analysis of FITC-inulin
samples, a standard curve was generated and used for calculating
[FITC-inulin]. All standards and urine samples were run in
triplicate; most plasma samples were run in duplicate. Very small blood
samples (~20 µl) were taken to minimize the effect of plasma
sampling on blood pressure. Occasionally, a plasma sample was too small
to analyze more than once.
Statistics. All data are presented as means ± SE. Groups were compared using the unpaired t-test, with P < 0.05 considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Other than the hypertensive phenotype, no other overt physical
differences were observed between wild-type mice and
M1/. When animals were on the normal-salt diet, the
mean BWs of M1+/+ (24 ± 0.5 g,
n = 18) and M1/ (25 ± 1.0 g, n = 18) were not significantly different. The kidney weights of M1+/+ (0.29 ± 0.01 g,
n = 16) and M1/ (0.30 ± 0.02 g, n = 17) were also similar. The high-salt
diet did not significantly affect the BWs (M1+/+ 24 ± 1.0 g, n = 5; M1/ 24 ± 0.5 g, n = 9) or kidney weights
(M1+/+ 0.30 ± 0.01 g, n = 5;
M1/ 0.32 ± 0.01 g, n = 8)
of M1+/+ or M1/. Because
M1+/+ and M1/ fed the same diet
(normal or high salt) exhibited similar weight gains with age, it is
assumed that they ingested equivalent amounts of mice chow.
MAP.
In the present study, measurements of MAP were made in anesthetized
mice. Although the depth of anesthesia was difficult to determine, a
positive correlation between GFR and MAP was observed when MAP was <80
mmHg. Because low perfusion pressure affects autoregulation, we
excluded data from further analysis if the average MAP during the
collection period was <80 mmHg. It was found that eight mice (of 49)
had a MAP of <80 mmHg. Table 1 shows the
MAP in M1+/+ and M1/ during the
equilibration periods under euvolemic, volume-expanded, and high-salt
diet conditions. During the euvolemic equilibration periods, the MAP in
M1/ was significantly higher than that in
M1+/+. However, during the volume-expanded equilibration
period, the MAP in M1+/+ was significantly higher than
the M1+/+ euvolemic value, whereas the MAP in
M1/ was not significantly different from the
M1/ euvolemic value. The MAP in neither
M1+/+ nor M1/ was significantly
affected by treatment with a high-salt diet.
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GFR.
Figure 1 shows the GFR under euvolemic
and acutely volume-expanded conditions for M1+/+ and
M1/. Under euvolemic conditions, the GFRs in
M1+/+ and M1/ did not differ
significantly. For M1+/+, GFR was significantly higher
under volume-expanded conditions (2.5 ± 0.4 ml · min1 · 100 g BW1, n = 6) compared with euvolemic
conditions (1.3 ± 0.2 ml · min1 · 100 g BW1, n = 8; P < 0.02).
Similarly, for volume-expanded M1/, GFR (1.4 ± 0.1 ml · min1 · 100 g
BW1, n = 7) was significantly higher than
in euvolemic M1/ (1.0 ± 0.1 ml · min1 · 100 g BW1, n = 6; P < 0.05).
However, the GFR in volume-expanded M1+/+ was
significantly higher than the GFR in volume-expanded
M1/ (P < 0.02). There was no
significant effect of the high-salt diet on the GFR of either genotype
(data not shown: M1+/+ 1.0 ± 0.1 ml · min1 · 100 g BW1, n = 5; M1/
0.8 ± 0.2 ml · min1 · 100 g BW1, n = 9).
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Na+ handling in
M1/.
Figure 2, A and B,
shows the effects of acute and chronic volume expansion on
Na+ excretion (UNaV) and fractional excretion
of Na+ (FENa) in M1+/+ and
M1/. Plasma [Na+] data are shown in
Table 2. Under conditions of volume
expansion, the UNaV in M1+/+ was
significantly higher (4.3 ± 1.1 µeq · min1 · 100 g BW1, n = 10) than that observed under
euvolemic conditions (0.3 ± 0.1 µeq · min1 · 100 g BW1, n = 8; P < 0.01).
Similarly, the UNaV in M1/ was
significantly higher under volume-expanded conditions (2.7 ± 0.6 µeq · min1 · 100 g BW1, n = 9) compared with euvolemic
conditions (0.3 ± 0.1 µeq · min1 · 100 g BW1, n = 8; P < 0.002). There were no genotypic differences in UNaV under
volume-expanded or euvolemic conditions. There was no significant effect of the high-salt diet on UNaV for either genotype
(data not shown), with UNaV averaging 0.4 ± 0.1 µeq · min1 · 100 g BW1 (n = 5) in M1+/+ and
0.6 ± 0.2 µeq · min1 · 100 g BW1 (n = 5) in M1/.
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1+/+ (0.15 ± 0.03%, n = 8) and M1/ (0.23 ± 0.07%, n = 5). Both M1+/+ and M1/ exhibited
higher FENa on volume expansion compared with their respective euvolemic values (P < 0.02;
P < 0.001); however, the FENa in
volume-expanded M1/ (1.93 ± 0.35%,
n = 5) was significantly greater than that in volume-expanded M1+/+ (0.83 ± 0.29%,
n = 6; P < 0.04). FENa
tended to be elevated in mice fed the high-salt diet (data not shown)
compared with the normal diet for both M1+/+ (0.29 ± 0.09%, n = 5) and M1/ (1.08 ± 0.63%, n = 9), although the increases were not
significant. No significant differences in plasma [Na+]
were observed between groups.
K+ handling in
M1/.
Figure 3, A and B,
shows the rate of K+ excretion (UKV) and the
fractional excretion of K+ (FEK), respectively,
for M1+/+ and M1/ under euvolemic and
acute volume-expanded conditions. For M1+/+, the
UKV in the euvolemic group was 0.9 ± 0.2 µeq · min1 · 100 g BW1 (n = 8), whereas the
UKV in the volume-expanded group was significantly higher
at 2.7 ± 0.4 µeq · min1 · 100 g BW1 (n = 9; P < 0.05).
For M1/, the UKV under euvolemic
conditions was 0.5 ± 0.2 µeq · min1 · 100 g BW1 (n = 7), whereas the
UKV during volume expansion was significantly greater
(1.2 ± 0.1 µeq · min1 · 100 g
BW1, n = 9; P < 0.05).
Although the UKV in M1+/+ and
M1/ did not differ significantly during euvolemia,
UKV in volume-expanded M1/ was
significantly less than that in volume-expanded M1+/+
(P < 0.01). There was no effect of the high-salt diet
on UKV for any treatment group (data not shown), averaging
0.5 ± 0.1 µeq · min1 · 100 g BW1 (n = 5) in M1+/+ and
0.3 ± 0.1 µeq · min1 · 100 g BW1 (n = 9) in M1/.
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1+/+ and
M1/. With volume expansion, the FEK in
M1+/+ was 33 ± 7% (n = 5), a
value significantly higher than the FEK for euvolemic
M1+/+ (13 ± 2%, n = 8;
P < 0.01). However, the values of FEK for
euvolemic M1/ and volume-expanded
M1/ were not significantly different (12 ± 4, n = 5 and 19 ± 2%, n = 5, respectively). Treatment with the high-salt diet did not alter
FEK (data not shown: M1+/+ 12 ± 3, n = 5; M1/ 10 ± 2%,
n = 9).
Plasma [K+] data are shown in Table 2. Although plasma
[K+] values tended to be lower in both
M1+/+ and M1/ under volume-expanded
conditions, this decrease achieved statistical significance only in
M1+/+ (P < 0.05). There were no
significant differences in plasma [K+] for either
genotype on the high-salt diet (M1+/+ 5.1 ± 0.2, n = 5; M1/ 5.1 ± 0.3 mM,
n = 9).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although BKCa are expressed in several types of renal
cells (10, 11, 20), the role of BKCa-1 with
respect to renal function has not been investigated. The results of
this study provide several novel findings related to renal function in
BKCa-1 knockout mice. In the euvolemic conditions of
these experiments, no genotype-related differences were found in
excretion rates of inulin, Na+, or K+. In
contrast, with acute volume expansion, 1 knockout mice exhibited a
depressed GFR and FEK response, and an increased
FENa response, compared with M1+/+.
Therefore, BKCa, in conjunction with its 1 auxiliary
subunit, may be an important contributor to the maintenance of
electrolyte balance during acute volume expansion.
MAP.
1 Knockout mice, now studied by several groups of investigators,
express moderate but significant hypertension. Brenner et al.
(2) have reported that M1/ (C57BL/6
strain) were hypertensive by ~20 mmHg. Using a different M1/ model (129/SvJ strain), Plüger et al.
(24) reported that MAP was elevated by ~14 mmHg. Both of
these measurements were made in conscious mice using arterial
catheters. In the anesthetized (C57BL/6) mice in the present study,
M1/ were hypertensive by ~11 mmHg under euvolemic
conditions, whereas the MAP in M1/ and
M1+/+ was similar when the animals were volume expanded.
Volume handling. Because the FITC-inulin method only requires 20 µl of plasma, we were able to obtain accurate GFR measurements while avoiding the hypotensive effects of sampling blood. Hence, the values for GFR in this study correspond well with previously reported values (3, 17, 30).
Consistent with previous studies in rats (8) and mice (3, 5), the GFRs in both M1+/+ and
M1/ were significantly higher in the volume-expanded
groups compared with the euvolemic groups. However, the GFR in
volume-expanded M1/ was significantly less than that
in volume-expanded M1+/+. This was not related to
perfusion pressure because the MAPs in M1+/+ and
M1/ did not differ during volume-expanded
conditions. The failure of the GFR in M1/ to
appropriately respond to volume expansion implies that the 1-subunit
of BKCa has an important role in mediating the renal response to an increased volume load.
The reason for the attenuated GFR response to volume expansion in
M1/ is not understood. However, a hemodynamic effect
is likely because BKCa are present in both renal afferent
arterioles (4, 6) and glomerular mesangial cells
(25, 27, 28). In afferent renal arterioles,
BKCa play a relatively minor role in opposing constriction
(4), whereas in mesangial cells BKCa are a
major component of the counteractive response to constriction
(28). In addition, the 1-subunit is present in human
mesangial cells (24a), which are phenotypically
similar to smooth muscle and express an abundance of BKCa.
When activated by ANP, BKCa have a role in relaxing
glomerular mesangial cells, which can contribute to an elevated GFR by
increasing the capillary surface area available for filtration
(12, 28). This notion is consistent with a recent finding
in our laboratory that the 1-subunit is required for PKG activation
of mesangial BKCa (14). Therefore, an
attenuated GFR response to volume expansion can be explained by the
absence of the 1, which renders the mesangial BKCa less
responsive to ANP.
If the 1-subunit plays a role in promoting the vascular response to
ANP, M1/ would be expected to exhibit acute
hypertension with volume expansion. A recent study by Holtwick et al.
(9), using a mouse model with a smooth muscle-selective
deletion of guanylyl cyclase, demonstrated that acute vascular volume
expansion caused a rapid increase in the blood pressure of these
knockout mice. This hypertensive response would be expected if the
response to ANP is attenuated; however, in this study we observed no
such response in arterial pressure. The fact that arterial pressure in
M1/ was not influenced by volume expansion suggests
that the 1-subunit does not have a role in the vascular response to
ANP. Whereas BKCa may be the primary effector for
cGMP-mediated relaxation of mesangial cells (28), vascular
smooth muscle may have a variety of additional cGMP-mediated responses
leading to relaxation (15).
Alternatively, it is possible that the absence of the 1-subunit
causes the mesangial cells to be less responsive to either a
Ca2+ increase or stretch that occurs with volume expansion.
Although BKCa have been shown to be stretch activated in
some cells (22, 29), the potential role of the
1-subunit in this process has not been investigated.
Na+ handling in
M1/.
Like the GFR, the UNaV was similar in M1+/+
and M1/ under euvolemic conditions. However, even
under volume-expanded conditions, the UNaV in
M1/ was not significantly different from that of
M1+/+. The fact that the GFR in volume-expanded
M1/ was attenuated whereas the UNaV
approached a normal rate implies that changes in Na+
reabsorption account for the majority of the Na+ excretory
response to volume expansion in M1/. Indeed, the
FENa in M1/ was significantly greater
than that in M1+/+, indicating that
M1/ were able to compensate for decreased filtered
Na+ by reducing Na+ reabsorption. This is
consistent with previous studies showing that volume expansion causes a
decrease in distal Na+ reabsorption in addition to its
hemodynamic effects (13, 26).
K+ handling in
M1/.
Consistent with previous studies (1, 3, 26), the
UKV and FEK in wild-type mice were
substantially greater in the volume-expanded condition. However, in
M1/, the FEK was statistically the same
in the euvolemic and volume-expanded groups. Similar to
M1+/+, the UKV in M1/ was
significantly greater in the volume-expanded group compared with the
euvolemic group. However, in the volume-expanded condition, the
UKV in M1/ was significantly less than
the UKV in M1+/+. Our experimental design
(unpaired data) does not permit genotypic comparisons of the changes in
UKV from baseline. Therefore, we cannot draw any
conclusions about relative increases from baseline. For example, there
was a genotypic difference in the volume-expanded but not euvolemic
groups with respect to UKV; however, because of the low
values and the baseline variability in UKV in the euvolemic groups, it is possible that there may be similar fold-increases in UKV with volume expansion in M1+/+ and
M1/ that were undetectable.
1/ may reflect a role for
BKCa to promote K+ efflux from cells of the
distal nephron during high volume flow. In support of this notion, Woda
et al. (31) have recently shown that flow-mediated
K+ secretion in rabbit cortical collecting duct (CCD) is
mediated by BKCa. Moreover, Lu et al. (21)
provided evidence for an additional K+ secretory channel in
the CCD of ROMK (Kir1.1) knockout mice. BKCa, described as
stretch activated in the rat and rabbit CCD (22) as well
as the rabbit medullary thick ascending limb (29), may be
activated by high-volume-induced pressure on the cell membrane. Our
data specifically implicate the 1-subunit of the BKCa
channel as an important component in the mediation of K+
secretion under conditions of volume expansion. However, it is not
known whether the 1-subunit, either alone or with other
-subunits, is associated with the BK- in the CCD.
An alternative explanation for the diminished K+ secretory
response to volume expansion in M1/ is that the
compensatory reduction in Na+ reabsorption decreased the
driving force for K+ secretion. This would be true if the
reduction in Na+ reabsorption resulted in a less negative
membrane potential in the CCD, where the predominant amount of
K+ is secreted. However, to our knowledge, there is no
evidence that ANP (the major hormone responding to volume expansion)
affects membrane potential or K+ secretion in the CCD. A
study by Zeidel et al. (32) demonstrated that ANP
inhibited potential-stimulated Na+ uptake in the inner
medullary collecting duct (IMCD); however, little or no K+
secretion occurs in the IMCD. In addition, a study using ANP transgenic
(overexpressing) mice demonstrated enhanced K+ excretion in
response to volume expansion (5). Although it is possible
that the diminished K+ secretory response in
M1/ is due to a decrease in Na+
reabsorption, for the reasons stated above, a primary defect in
K+ secretion is the best explanation for this result.
Effect of a high-salt diet.
Although the high-salt diet did not significantly affect GFR or the
rates of Na+ and K+ excretion, it did tend to
increase Na+ excretion and decrease K+
excretion compared with the normal diet. This result is consistent with
the low aldosterone levels expected with a high-salt diet. The fact
that M1+/+ and M1/ had similar
responses to the high-salt diet indicates that the loss of the
BKCa-1 does not alter the compensatory renal response. In addition, the finding that MAP in M1/ was not
increased with the high-salt diet indicates that the hypertension
described for M1/ is not salt sensitive.
1 in the renal response to volume expansion.
BKCa-1 may have a role in the glomerulus to mediate an
elevated GFR during volume expansion and could potentially be important
in the distal nephron for the elevation of K+ secretion
associated with high flow rates. To more clearly define these roles,
future studies must elucidate the specific pathway(s) involved in the
renal responses to volume expansion and the specific expression
patterns of the -subunits associated with BKCa within the kidney.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Robert Brenner and Richard Aldrich (Stanford
Univ.) for graciously supplying the BKCa-1 mice used in
this study. We also thank Drs. Tong Wang and Gerhard Giebisch (Yale
Univ.) for advice and guidance regarding the surgical procedures for
analyzing renal function in mice.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants RO1-DK-49561 (to S. C. Sansom) and 1T32-HL-0788 (Cardiovascular Research Training Grant; to J. L. Pluznick).
Address for reprint requests and other correspondence: S. C. Sansom, Dept. of Physiology and Biophysics, 984575 Univ. of Nebraska Medical Ctr., Omaha, NE 68198-4575 (E-mail: ssansom{at}unmc.edu).
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. Section 1734 solely to indicate this fact.
First published March 4, 2003;10.1152/ajprenal.00010.2003
Received 9 January 2003; accepted in final form 26 February 2003.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.02). BW, body weight.
