1 Vascular Biology Center, Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912; and Departments of 2 Medicine (Nephrology) and Molecular Biology and Biophysics and of 3 Medicine (Nephrology) and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
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The present studies were performed
to determine the contribution of EP2 receptors to renal
hemodynamics by examining afferent arteriolar responses to
PGE2, butaprost, sulprostone, and endothelin-1 in
EP2 receptor-deficient male mice (EP2/
).
Afferent arteriolar diameters averaged 17.8 ± 0.8 µm in
wild-type (EP2+/+) mice and 16.7 ± 0.7 µm in
EP2
/
mice at a renal perfusion pressure of 100 mmHg.
Vessels from both groups of mice responded to norepinephrine (0.5 µM)
with similar 17-19% decreases in diameter. Diameters of
norepinephrine-preconstricted afferent arterioles increased by 7 ± 2 and 20 ± 6% in EP2+/+ mice in response to 1 µM PGE2 and 1 µM butaprost, respectively. In contrast,
afferent arteriolar diameter of EP2
/
mice decreased by
13 ± 3 and 16 ± 6% in response to PGE2 and
butaprost. The afferent arteriolar vasoconstriction to butaprost in
EP2
/
mice was eliminated by angiotensin-converting enzyme inhibition. Sulprostone, an EP1 and EP3
receptor ligand, decreased afferent arteriolar diameter in both groups;
however, the vasoconstriction in the EP2
/
mice was
greater than in the EP2+/+ mice. Endothelin-1-mediated
afferent arteriolar diameter responses were enhanced in
EP2
/
mice. Afferent arteriolar diameter decreased by
29 ± 7% in EP2
/
and 12 ± 7% in
EP2+/+ mice after administration of 1 nM endothelin-1.
These results demonstrate that the EP2 receptor mediates a
portion of the PGE2 afferent arteriolar vasodilation and
buffers the renal vasoconstrictor responses elicited by EP1
and EP3 receptor activation as well as endothelin-1.
prostaglandins; endothelin; kidney; microcirculation
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INTRODUCTION |
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THE REGULATION OF WATER and electrolyte homeostasis is dependent on the renal hemodynamic and tubular transport actions of PGE2 (5, 14, 25, 42). PGE2 is the major renal cyclooxygenase (COX)-derived metabolite in the kidney and the PGE2 receptors (EP) are abundantly expressed in the kidney (5, 7, 8). Four seven-transmembrane-spanning domain, G protein-coupled EP receptors have been identified (5, 7, 8). The intracellular signaling mechanisms for the EP receptors have been characterized and activate mechanisms that would either relax or contract smooth muscle (5, 14). Overall, PGE2 has been demonstrated to increase renal blood flow and glomerular filtration rate but the contribution of EP receptors to the control of renal hemodynamics remains unresolved.
An important role for the EP2 receptors in regulating fluid and electrolyte homeostasis has been suggested by studies in mice with targeted disruption of these receptors (21, 38, 43). Disruption of the EP2 receptor in mice does not alter renal blood flow but does unmask a systemic vasoconstriction in response to PGE2 (3, 43). These mice lacking EP2 receptors develop salt-sensitive hypertension (20). Thus further investigation of the renal microvascular actions of PGE2 is of extreme interest in these mice. The purpose of the present study was to determine the contribution of EP2 receptors to renal hemodynamics by examining afferent arteriolar responses to PGE2, selective EP receptor agonists, and endothelin-1 in mice lacking EP2 receptors.
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MATERIALS AND METHODS |
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Chemical reagents. Sulprostone, PGE2, and butaprost were purchased from Cayman Chemical. Norepinephrine (Levophed) was obtained from Winthrop Pharmaceuticals. Endothelin-1 was purchased from Phoenix Pharmaceuticals. Enalaprilat was a gift from Merck Sharp and Dohme. Indomethacin and all other reagents were purchased from Sigma.
Animal preparation.
EP2 receptor-deficient mice were generated at
Vanderbilt University as previously described (21).
F2 wild-type (EP2+/+) and EP2-null
(EP2/
) mice were littermates produced from
intercrossing F1 heterozygous (EP2+/
) mice.
All mice were weaned at 3 wk of age and fed a standard chow diet.
Genotypes of the mice were routinely determined by Southern analysis of
genomic tail DNA. The wild-type (4.3 kb) and recombinant (7.5 kb)
XbaI fragments were identified by using a 3'
XbaI/SacI fragment as a probe. Animals were
housed for at least 2 wk at the Tulane University School of Medicine vivarium. The Vanderbilt University and Tulane Advisory Committee for
Animal Resources approved all experiments, and the procedures followed
were in accordance with institutional guidelines.
Vascular preparation.
Experiments were performed in male EP2+/+ and
EP2/
mice weighing an average of 33 ± 1 and
32 ± 1 g, respectively. Mice were anesthetized with a
combination of thiobutabarbital (Inactin; 100 mg/kg ip) and ketamine
(Ketaset; 10 mg/kg ip), and a midline abdominal incision was made. The
right renal artery was cannulated via the superior mesenteric artery,
and the kidney was immediately perfused with Tyrode solution containing
6% albumin and a mixture of L-amino acids
(15). All protocols were conducted in the juxtamedullary microvascular preparation perfused with the cell-free Tyrode solution containing 6% albumin. We previously demonstrated that the main difference between a cell-free and red blood cell-containing solution is that nitric oxide levels are elevated in a cell-free perfusate (16). The Tyrode solution was stirred continuously in a
closed reservoir that was pressurized by a 95% O2-5%
CO2 tank. The kidney was removed from the mouse and
maintained in an organ chamber at room temperature throughout the
isolation and dissection procedure. The juxtamedullary microvasculature
was isolated for study as previously described (15). The
organ chamber was then warmed, and the tissue surface was continuously
superfused with Tyrode solution containing 1% albumin at 37°C. Renal
artery perfusion pressure, measured at the tip of the cannula, was set
to 100 mmHg.
Afferent arteriolar diameter response to PGE2. After a 20-min equilibration period, baseline diameter measurements of the afferent arteriole were made. Norepinephrine (0.5 µM) was added to the perfusate to elevate basal vascular tone. The endogenous ligand PGE2 (1 µM) was added to the perfusate, and vessel diameter changes were monitored for 5 min. In additional experiments, the influence of the renin-angiotensin system on the afferent arteriolar diameter response was evaluated. For these studies, the angiotensin- converting enzyme inhibitor enalaprilat (1 mg ip) was administered to the mice (17). One hour after the injection, the kidney was harvested and the afferent arteriolar response to PGE2 was determined as described above.
Afferent arteriolar response to the EP receptor activation with
butaprost or sulprostone.
After a 20-min equilibration period and baseline diameter
measurements, the afferent arteriole was preconstricted with
norepinephrine (0.5 µM). The arteriole was subsequently exposed to
increasing concentrations of an EP2 receptor-selective
ligand, butaprost (0.01-1 µM) (7, 8, 14, 25), and
diameter change was monitored for 5 min at each concentration. In a
separate series, the afferent arteriolar diameter response to butaprost
was determined in enalaprilat-treated EP2+/+ and
EP2/
mice.
Involvement of the EP2 receptor in the afferent arteriolar vasoconstrictor response to endothelin-1. After a 20-min equilibration period, baseline diameter measurements of the afferent arteriole were made. Endothelin-1 (0.1-10 nM) was then administered in increasing concentrations, and diameter changes were monitored. In a separate series, the concentration-response profile to endothelin-1 was determined in the presence of the nonselective COX inhibitor indomethacin (10 µM) (15). Indomethacin was added to the perfusate and superfusate for 20 min to ensure complete tissue blockade (15).
Statistical analysis. In all experiments, steady-state diameter was attained by the end of the second minute, and the average diameter of the third to fifth minute of each treatment period was used for graphical representation. Data are presented as means ± SE. The basic design for each treatment protocol is a prospective randomized controlled trial with repeated measures over time for the independent groups. Standard parametric change-from-baseline analyses within each group were conducted for each of the outcome measures. Change scores were computed and used in between-group hypothesis testing (ANOVA). Post hoc multiple comparisons were made using standard statistical Student-Newman-Keuls methods to adjust the "comparison-wise" error rate. A value of P < 0.05 was considered statistically significant.
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RESULTS |
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Afferent arteriolar diameter response to PGE2 in
EP2+/+ and
EP2/
mice.
Consistent with previous reports, body weight was similar between the
groups and averaged 33 ± 1 g in EP2+/+ and
32 ± 1 g in EP2
/
mice. Afferent arteriolar
diameter at a renal perfusion pressure of 100 mmHg was unaltered by the
absence of EP2 receptors. Diameter of the afferent
arteriole averaged 16.7 ± 0.7 µm (n = 39) in
EP2
/
compared with 17.8 ± 0.8 µm
(n = 40) in EP2+/+ mice. Norepinephrine
decreased preglomerular diameter to the same extent in
EP2+/+ and EP2
/
mice. Afferent arteriolar
diameter decreased by 17 ± 3% (n = 29) in
EP2+/+ and 18 ± 4% (n = 27) in
EP2
/
mice in response to perfusion of 0.5 µM norepinephrine.
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Afferent arteriolar diameter response to butaprost in
EP2+/+ and
EP2/
mice.
Figure 3 depicts the preglomerular
vascular response to the selective EP2 receptor ligand
butaprost in EP2+/+ and EP2
/
mice. The
diameter of norepinephrine-precontracted afferent arterioles increased
by 20 ± 6% (n = 6) in response to 1 µM
butaprost in EP2+/+ mice. Similar to the response to
PGE2, superfusion of 1 µM butaprost constricted the
preglomerular vessel caliber by 16 ± 6% (n = 6)
in mice lacking EP2 receptors. Additional experiments were
performed to determine the involvement of the renin-angiotensin system
to the butaprost-mediated afferent arteriolar vasoconstriction in
EP2
/
mice. After enalaprilat treatment, afferent
arteriolar diameters were not different from untreated mice and
averaged 18 ± 2 µm (n = 5) in
EP2+/+ and 17 ± 1 µm (n = 5) in
EP2
/
mice. Angiotensin-converting enzyme inhibition
eliminated the preglomerular vasoconstrictor response in
EP2
/
mice but did not significantly alter the
vasodilatory response to butaprost in EP2+/+ mice (Fig. 4).
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Afferent arteriolar diameter response to sulprostone in
EP2+/+ and
EP2/
mice.
The preglomerular vascular response to EP1 and
EP3 receptor activation with sulprostone is depicted in
Fig. 5. The afferent arteriolar diameter
response to sulprostone was significantly greater in
EP2
/
mice compared with that of EP2+/+
mice. Sulprostone (1 µM) decreased afferent arteriolar diameter by
7 ± 2% (n = 6) in EP2+/+ mice and by
17 ± 3% (n = 5) in mice lacking EP2
receptors.
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Enhanced afferent arteriolar reactivity to endothelin-1 in
EP2/
mice.
Figure 6 depicts the afferent
arteriolar vasoconstrictor response to endothelin-1 in
EP2+/+ and EP2
/
mice. Afferent arteriolar diameter decreased after superfusion of endothelin-1 and reached a
steady-state diameter by the end of the second minute. The
preglomerular vascular response to endothelin-1 was significantly
enhanced in mice lacking EP2 receptors. Afferent arteriolar
diameter decreased by 12 ± 7% (n = 6) in
EP2+/+ and 29 ± 7% (n = 5) in
EP2
/
mice after administration of 1 nM endothelin-1.
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DISCUSSION |
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Studies in mice lacking EP2 receptors point to a
critical role for these receptors in the maintenance of renal blood
flow and water homeostasis (21, 38, 43). The present study
focused on the contribution of the EP2 receptor to the
control of renal microvascular function. We found that PGE2
or the EP2 receptor ligand butaprost when administered to
wild-type mice resulted in an increase in afferent arteriolar diameter.
In contrast, PGE2 and butaprost decreased afferent
arteriolar vessel caliber in EP2/
mice. The
vasoconstriction in response to PGE2 and butaprost in mice
lacking EP2 receptors was eliminated by
angiotensin-converting enzyme inhibition. These findings suggest that
PGE2-mediated stimulation of the renin-angiotensin system
in EP2
/
mice was responsible for the afferent
arteriolar vasoconstriction observed in these mice. In addition to the
afferent arteriolar vasoconstrictor response to the EP1 and
EP3 receptor agonists, sulprostone was enhanced in mice
lacking EP2 receptors. Endothelin-1 also resulted in a greater decrease in preglomerular diameter in
EP2
/
mice. The enhanced vasoconstrictor response
to endothelin-1 in mice lacking EP2 receptors appears to be
COX-dependent because indomethacin eliminated this difference between
EP2+/+ and EP2
/
mice. Overall, the results
of these studies suggest that EP2 receptors help sustain renal blood flow.
The biological actions of PGE2 are mediated via activation
of one of four EP receptors (5). EP receptors are abundant
throughout the kidney and are expressed in the renal microcirculation
(5, 31, 37, 43). Molecular and pharmacological
characterization of four different EP receptors, designated
EP1-4, have been completed (5, 39).
Activation of vascular EP1 and EP3 receptors would be expected to contract smooth muscle cells. EP1
receptors act via the inositol trisphosphate (IP3),
diacylglycerol (DAG), and protein kinase C (PKC) pathway (4, 12,
40), and EP3 receptors decrease cAMP and increase
rho (1, 2, 24). Activation of either
EP2 or EP4 receptors results in an increase in
rabbit and rat preglomerular vessel cAMP levels and results in
relaxation of vascular smooth muscle (5, 10, 17, 33). In
many studies, PGE2 has been demonstrated to increase renal
blood flow (5, 14, 25); however, under certain
experimental conditions renal vasoconstriction has been observed during
administration of PGE2 (19). These opposing
results suggest that renal microvessels contain multiple EP receptors.
Although all four EP receptors appear to be expressed in the renal
microvasculature (23, 31, 37, 43), there is still
controversy on this point, because half of these studies failed to find
mRNA expression for all four EP receptors (31, 37). The
fact that we observed an increase in afferent arteriolar diameter in
EP2+/+ mice but a decrease in vessel caliber in
EP2/
mice in response to PGE2 supports the
concept that the renal microcirculation is modulated by multiple PG
receptor subtypes.
There is controversy regarding the EP receptor subtype that is
responsible for the PGE2-mediated increase in renal blood
flow. Recent studies have provided experimental evidence that the
EP4 receptor is responsible for the dilator response to
PGE2 (31, 37); however, these studies did not
directly determine the actions of butaprost on afferent arteriolar
diameter or renal blood flow. Interestingly, one of these studies did
demonstrate that butaprost opposed the afferent arteriolar constrictor
actions of angiotensin by 40% and attributed this response to
EP4 receptor stimulation because the study failed to find
EP2 mRNA expression in isolated renal microvessels
(37). However, this interpretation is at variance with the
pharmacological characterization of cloned receptors that suggests that
butaprost does not stimulate EP4 receptor-evoked responses
at concentrations up to 10 µM (26). Experimental studies in gene-disrupted mice performed by Audoly et al. (3)
found that baseline renal blood flow was not different between
EP2+/+ and EP2/
mice and that
EP2
/
mice had a vasodilator response to a single dose
of PGE2 similar to mice with EP2 receptors. In agreement with these findings, we did not observe a difference in
baseline afferent arteriolar diameter between EP2+/+ and
EP2
/
mice. On the other hand, we observed a
vasoconstriction to PGE2 and butaprost in mice lacking an
EP2 receptor. The reason for this difference is unknown.
One possible explanation is that the present study investigates
afferent arterioles of the juxtamedullary area that give rise to the
vasa recta in the medullary circulation. Previous studies have
demonstrated that COX inhibition has a greater effect on medullary
compared with outer cortical blood flow (11, 14, 32).
Other studies also noted differences in responses to PGE2
between superficial and juxtamedullary afferent arterioles (14,
29, 35). The renal vascular distribution of the EP2 receptor and other EP receptors is presently not known. Our studies provide evidence that the EP2 receptor does participate in
the renal hemodynamic response to PGE2 and butaprost (Fig.
7).
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One very interesting finding of the present study is that afferent
arterioles constricted in response to PGE2 and butaprost in
mice lacking EP2 receptors. We further demonstrated that
angiotensin-converting enzyme inhibition eliminated the afferent
arteriolar constrictor response to PGE2 and butaprost in
EP2/
mice. Butaprost-mediated stimulation of the
renin-angiotensin system may be due to prostaglandin I2
(IP) receptor activation because butaprost activates IP receptors at
micromolar concentrations (22). Butaprost activation of IP receptors is consistent with the observation that prostacyclin is a
mediator of COX-dependent renin release (41). These
findings do not preclude the possibility that EP4 receptors
participate in PGE2-evoked renin release as well. In
contrast to the effects of butaprost, Tang et al. (37)
demonstrated that the EP4 receptor agonist
11-deoxy-PGE1 completely reversed the afferent arteriolar vasoconstriction to angiotensin II, suggesting EP4 receptor
activity opposes the renin-angiotensin system (37). It is
important to note that these experiments were conducted in the
hydronephrotic kidney that lacks tubules and interactions among the
macula densa, juxtaglomerular apparatus, and vascular smooth muscle.
Therefore, prostaglandin activation of the renin-angiotensin system
would not occur under this experimental setting. Nevertheless, we did observe preglomerular vasodilation in response to PGE2
during angiotensin- converting enzyme inhibition in
EP2
/
mice. This finding supports the concept that
EP4 receptors on preglomerular vessels participate in
maintaining renal blood flow.
As mentioned above, butaprost is reported to be an
EP2-selective agonist and should not have influenced renal
microvessel caliber in mice lacking EP2 receptors. IP
receptor activation and renin release could mediate the
butaprost-mediated vasoconstriction. Although butaprost has a much
lower affinity for the EP4 receptor (5),
butaprost actions on the EP4 receptor may be unmasked in
mice lacking EP2 receptors. PGE2 also
stimulates renal renin release (13, 20), and the
EP4 receptor is presently the best candidate for mediating
this response (5). PGE2 stimulates cAMP and
renin release from juxtaglomerular cells, and intrarenal renin mRNA is
not different between wild-type and EP2/
mice (38). In addition, EP4 but not EP2
receptors are abundantly expressed in glomeruli (6, 9,
36). Thus the results of the present study support the concept
that PGE2 activation of the renin-angiotensin system
opposes the PGE2-mediated increase in renal blood flow and
is not EP2 receptor mediated and may be mediated by
EP4 and/or IP receptor activation (Fig. 7). We cannot rule
out the possibility that activation of other vasoactive pathways might
participate in the PGE2-mediated afferent arteriolar
vasoconstriction observed in EP2
/
mice.
The afferent arteriolar response to sulprostone was assessed in mice lacking EP2 receptors to determine whether EP2 receptors opposed EP1 and EP3 receptor-mediated vasoconstriction. Sulprostone decreased afferent arteriolar diameter to a greater extent in mice lacking EP2 receptors compared with EP2+/+ mice. This finding confirms that EP1 or EP3 receptor activation results in an increase in renal vascular resistance (Fig. 7) (5, 31, 37). There is still controversy regarding which EP receptor is responsible for the vasoconstrictor response to PGE2. A recent study demonstrated afferent arteriolar constriction in response to the EP1/3-selective agonist sulprostone, but this response was not blocked by the EP1 antagonist SC-51322 (37). These findings suggest that the EP3 receptor is primarily responsible for the renal vasoconstrictor response to PGE2. In contrast, evidence for EP1 but not EP3 receptors in rat preglomerular vessels has recently been demonstrated (31). Purdy and Arendshorst (31) did not observe inhibition of isoproterenol elevation of cAMP levels in renal microvessels by the EP3 agonist M&B28767. Interestingly, this same group has data that suggest that EP3 receptors are important to the control of renal hemodynamics in the mouse (3). Renal blood flow was elevated and the vasodilatory response to PGE2 was enhanced in mice that lack the EP3 receptor. Additionally, systemic administration of the EP3 agonist SC-46275 resulted in a prolonged elevation of arterial blood pressure in mice lacking EP2 receptors (43). The results of the present study demonstrate that EP2 receptors oppose the preglomerular vasoconstrictor response to sulprostone.
The contribution of endothelin-1 to the development of salt-sensitive
hypertension is well established (30, 34). Interestingly, mice that lack EP2 receptors develop hypertension when fed
a high-salt diet (21). Therefore, we investigated the
contribution of EP2 receptors to oppose the afferent
arteriolar vasoconstrictor response to endothelin-1. Afferent
arterioles from EP2 /
mice were more responsive to
endothelin-1 compared with EP2+/+ mice. Along these lines,
Oyekan and McGiff (28) demonstrated that the
endothelin-1-evoked decreases in renal blood flow and glomerular
filtration were enhanced by COX inhibition. In contrast, indomethacin
attenuated the increase in renal vascular resistance, the afferent
arteriolar decrease in diameter, and renal microvascular smooth muscle
cell calcium response to endothelin-1 (18, 27). The
results of the present study also suggest involvement of COX-derived
vasodilator and vasoconstrictor metabolites in the afferent arteriolar
response to endothelin-1. The enhanced response to endothelin-1
observed in mice lacking EP2 receptors was eliminated by
COX inhibition. Thus PGE2 activation of EP2
receptors and the resultant vasorelaxation oppose COX-mediated renal
vasoconstrictor mechanisms in response to endothelin-1.
In summary, afferent arteriolar diameter of EP2+/+
increased in response to PGE2 and butaprost, whereas
PGE2 and butaprost decreased the diameter of afferent
arterioles in EP2/
mice. The renal vasoconstriction to
butaprost in EP2
/
mice was eliminated by enalapril.
This observation supports the concept that the renin-angiotensin system
contributed to the PGE2-mediated vasoconstriction in
EP2
/
mice. Mice lacking EP2 receptors also
exhibited a greater vasoconstriction to the EP1 and
EP3 agonist sulprostone. Endothelin-1 elicited a greater
afferent arteriolar vasoconstrictor response in mice lacking
EP2 receptors. COX inhibition ameliorated this enhanced endothelin-1 response in EP2
/
mice. Overall, these
studies support the concept that EP2 receptors participate
in the maintenance of afferent arteriolar function.
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ACKNOWLEDGEMENTS |
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The work presented in this manuscript was conducted at the Tulane University School of Medicine in Dr. Imig's laboratory. The authors thank P. Diechmann and S. Brandon for technical assistance with the experimental studies. Assistance with the statistical analysis was provided by Dr. J. Dias at the Medical College of Georgia.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants DK-38226 (to J. D. Imig), HL-59699 (to J. D. Imig), GM-15431 (to R. M. Breyer), DK-46205 (to R. M. Breyer), and DK-37097 (to M. D. Breyer).
Address for reprint requests and other correspondence: J. D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500 (E-mail: jdimig{at}mail.mcg.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.
March 19, 2002;10.1152/ajprenal.00351.2001
Received 27 November 2001; accepted in final form 14 March 2002.
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