1 Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and 2 Department of Medicine, Duke University, and Durham Veterans Affairs Medical Centers, Durham, North Carolina 27705
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ABSTRACT |
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The relative contributions of
AT1A and AT1B receptors to afferent arteriolar
autoregulatory capability and afferent and efferent arteriolar
responses to ANG II are not known. Experiments were conducted in
kidneys from wild-type (WT) and AT1A/
mice utilizing the in vitro blood-perfused juxtamedullary nephron technique. Direct
measurements of afferent (AAD) and efferent arteriolar diameters (EAD)
were assessed at a renal arterial pressure of 100 mmHg. AAD averaged
14.8 ± 0.8 µm for WT and 14.9 ± 0.8 µm for
AT1A
/
mice. AAD significantly decreased by 7 ± 1, 16 ± 1, and 26 ± 2% for WT mice and by 11 ± 1, 20 ± 2, and 30 ± 3% for AT1A
/
mice (120, 140, 160 mmHg). AAD autoregulatory capability was not affected by the
absence of AT1A receptors. AAD responses to 10 nM ANG II
were significantly blunted for AT1A
/
mice compared with
WT (
22 ± 2 vs.
37 ± 5%). ANG II (0.1-10 nM)
failed to elicit any change in EAD for AT1A
/
mice. AAD
and EAD reductions in ANG II were blocked by 1 µM candesartan. We
conclude that afferent arteriole vasoconstrictor responses to ANG II
are mediated by AT1A and AT1B receptors,
whereas efferent arteriolar vasoconstrictor responses to ANG II are
mediated by only AT1A receptors in the mouse kidney.
afferent arteriole; efferent arteriole; juxtamedullary nephron; candesartan; autoregulation
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INTRODUCTION |
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THERE ARE AT LEAST TWO MAJOR angiotensin receptors: AT1 and AT2. The AT1 receptor is thought to mediate most of the actions of ANG II on renal hemodynamic and tubular function, including afferent and efferent arteriolar vasoconstriction (3, 9, 31), modulation of tubuloglomerular feedback sensitivity (16), sodium and fluid reabsorption (18), and growth and differentiation (29). Two subtypes of the AT1 receptors, designated AT1A and AT1B, have been identified in the rat (7, 12, 13, 23) and mouse (24). The AT1A receptor is thought to be the predominant renal form. Terada et al. (28) reported localization of the AT1 receptor mRNA in microdissected renal vascular segments (glomeruli, vasa recta bundle, and arcuate arteries) of the kidney by RT-PCR methods. Further studies identified AT1A and AT1B mRNAs in the same renal vascular structures, as well as the afferent arteriole (2, 7). Additionally, the AT1 receptor protein has been localized to the entire rat renal vasculature using immunohistochemical techniques and antibodies that recognize specifically the AT1A receptor (30) or both the AT1A and AT1B receptor subtypes (10, 17, 21, 30). The mRNA and protein expression profiles of the AT1 receptor subtypes have not been determined for the efferent arteriole. Furthermore, the contribution of the AT1A and AT1B receptors to the afferent and efferent arteriolar responses to ANG II have not been investigated.
The AT1A and AT1B receptors are pharmacologically indistinguishable from each other, and so it has not been possible to discriminate between the receptor subtype functions using pharmacological antagonists. The physiological effects of renal AT1A and AT1B receptor subtypes have yet to be elucidated, although the calcium signaling mechanisms of the AT1A and AT1B receptors appear to be identical in isolated cells (15, 32). The AT1A and AT1B receptor subtype localization, regulation, and function in various pre- and postglomerular microvascular segments may play an important part in the renal hemodynamic responses to ANG II in a variety of physiological and pathophysiological conditions.
Gene-targeted mice have proven to be a critical tool in defining the
role of each AT1A and AT1B receptor subtype in
vivo. AT1A/
mice have reduced blood pressure, lack a
systemic pressor response to exogenous ANG II, and exhibit mild renal
structural abnormalities that include slight papillary hypoplasia and
hyperplasia of renin-producing granular cells (11, 20,
26). Surprisingly, renal hemodynamics of wild-type (WT) and
AT1A
/
mice are similar, such that glomerular filtration
rate and renal plasma flow (6) and renal blood flow
(22) do not differ between anesthetized WT and
AT1A
/
mice; however, renal vascular resistance is lower in the AT1A
/
mice, paralleling the lower arterial
pressure (22). The reduction in renal blood flow produced
by ANG II in WT mice is similar to the reduction in renal blood flow
produced by 10-fold higher doses of ANG II in AT1A
/
mice (22). However, the renal microvascular segment
responsible for the ANG II responsiveness in AT1A
/
mice
could not be determined in these studies. Additionally, AT1A
/
mice lack a tubuloglomerular feedback mechanism
(25), which may result in an impaired renal autoregulatory
responsiveness in these mice.
The present studies were conducted to test the hypotheses that
AT1A/
receptor-deficient mice display impaired renal
afferent arteriolar autoregulatory responses and altered afferent and
efferent arteriolar ANG II sensitivity. To directly assess the renal
microvascular responses to changes in renal arterial perfusion pressure
and ANG II, vessels were studied in an intact tubular environment (5) using the mouse in vitro blood-perfused juxtamedullary nephron preparation.
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METHODS |
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Mouse in vitro blood-perfused juxtamedullary nephron technique.
Assessment of afferent and efferent arteriolar diameters was conducted
in kidneys from 49 adult male and female WT (n = 14 females; n = 4 males), AT1A+/
(n = 4 males), and AT1A
/
(n = 22 females; n = 5 males) mice
ranging from 3 to 7 mo of age that were breed in our colony at Duke
University. Forty-nine adult male Sprague-Dawley rats were used as
blood donors. Experiments were conducted using the mouse in vitro
blood-perfused juxtamedullary nephron technique, which is based on the
rat in vitro blood-perfused juxtamedullary nephron technique originally
developed by Casellas et al. (4). Kidneys were harvested
from mice under pentobarbital sodium anesthesia (50 mg/kg ip). The
renal artery was cannulated via the descending aorta under a dissecting
microscope and immediately perfused with a Tyrode buffer containing 51 g/l bovine serum albumin (98-99% albumin, Sigma) and a mixture of
L-amino acids at pH 7.4 as previously described in detail
(8). The cannula system includes a 27-gauge blunted
hypodermic needle for introduction into the renal artery, polyethylene
(PE)-10 tubing for blood perfusion, and PE-10 tubing for the
measurement of perfusion pressure. The tips of all of the tubing are in
close proximity to each other. A section of liver was removed from each
animal, immersed into liquid nitrogen, and stored at
70°C for
genotyping by Southern blot analysis as previously described
(11). The kidney was placed in a perfusion chamber at room
temperature for the dissection procedure, which included removal of the
ventral third of the kidney, reflection of the papilla, cutting open of
the renal veins, placement of 10.0 suture ties on the distal segments
of the large arteries, and removal of the connective tissue and pelvic
mucosa overlying the juxtamedullary cortical surface (Fig.
1A).
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Afferent arteriolar autoregulatory responses.
Afferent arteriolar diameters were monitored in response to elevations
in renal perfusion pressure in kidneys from female WT
(n = 6), AT1A+/ (n = 2),
and AT1A
/
(n = 6) mice. Afferent arteriolar diameters were measured during a 5-min control period at 100 mmHg. Renal perfusion pressure was increased in a stepwise fashion to
120, 140, and 160 mmHg as previously described for studies in the rat
kidney (27). The pressures were maintained at each level
for 3 min. Pressure was then returned to 100 mmHg for a 5-min recovery
period. In a subset of mice, ANG II dose responses were determined
after the recovery period, as described below.
Afferent arteriolar ANG II responses.
Afferent arteriolar diameters in kidneys from male and female WT
(n = 9 females; n = 2 males),
AT1A+/ (n = 4 females) and AT1A
/
(n = 14 females;
n = 3 males) mice were measured during superfusion with
ANG II. After a 5-min control period or recovery from the change in
perfusion pressure protocol, the kidneys were superfused sequentially
with 0.1, 1.0, and 10 nM ANG II for a period of 5 min for each
concentration. A recovery period of 5 min was then observed. Kidneys
were then superfused for 5 min with an AT1 receptor blocker
(1 µM candesartan), and the ANG II concentration-response
relationship was repeated in the same vessel from WT (n = 5), AT1A+/
(n = 2), and
AT1A
/
(n = 11) mice.
Afferent arteriolar ANG II time control responses.
Afferent arteriolar diameters were measured in kidneys from female
AT1A/
mice (n = 3) in response to 0, 0.1, 1.0, 10, and 0 nM ANG II for a period of 5 min for each
concentration. This protocol was repeated in the same vessels
to demonstrate that the vasculature responds to a second application of
ANG II.
Efferent arteriolar ANG II responses.
Efferent arteriolar diameters in kidneys from male and female WT
(n = 5 females; n = 2 males) and
AT1A/
(n = 5 females; n = 2 males) mice were measured during superfusion with ANG II. After a
5-min control period, the kidneys were superfused with 0.1, 1.0, and 10 nM ANG II for a period of 5 min for each concentration. A recovery
period of 5 min was then observed. Kidneys were then superfused for 5 min with an AT1 receptor blocker (1 µM candesartan). The
ANG II dose-response relationship was repeated in the same vessel in
all kidneys.
Data analysis. Afferent and efferent arteriolar luminal diameters were measured at 12-s intervals throughout the entire protocol. Plateau responses were determined by averaging data obtained during the final 2 min of each treatment period and used for statistical analysis. Statistical analyses were performed using SigmaStat statistical software on the raw data by one-way or two-way analysis of variance, followed by Tukey's test or paired t-test as appropriate. Baseline diameters were analyzed by unpaired t-test. A P value <0.05 was considered statistically significant. All data are presented as the means ± SE (n = no. of arterioles).
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RESULTS |
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Animals.
Body weights of the three genotypes of mice averaged 39 ± 2 g for WT (n = 18), 37 ± 5 g for
AT1A+/ (n = 4), and 33 ± 1 g for AT1A
/
(n = 27) mice. Body weights
of AT1A
/
mice were significantly smaller than those of
WT mice (P < 0.05).
Afferent arteriolar autoregulatory responses.
Afferent arteriolar baseline diameters were not significantly different
between WT (n = 6) and AT1A/
(n = 6) mice, averaging 14.8 ± 0.8 and 14.9 ± 0.8 µm, respectively. After stepwise increases in renal perfusion
pressure to 120, 140, and 160 mmHg, afferent arteriolar diameters
significantly decreased by 7 ± 1, 16 ± 1, and 26 ± 2% for WT mice and by 11 ± 2, 23 ± 5, and 30 ± 5%
for AT1A
/
mice, respectively (Fig.
2). Afferent arteriole diameters were
significantly reduced at each step increase in perfusion pressure in
kidneys of WT and AT1A
/
mice. Afferent arteriolar diameters were not significantly different during the recovery period
compared with baseline diameters in each group. Afferent arterioles
from AT1A+/
(n = 2) mice displayed a
similar pattern of response. Afferent arteriolar diameters for
AT1A+/
mice decreased 11, 25, and 31% of the baseline of
15.1 µm when renal perfusion pressure was increased from 100 to 120 to 140 to 160 mmHg, respectively. WT, AT1A+/
, and
AT1A
/
mice exhibited similar afferent arteriolar autoregulatory responses to increases in renal perfusion pressure. The
magnitude of the responses was not different between WT and AT1A
/
mice (P = 0.6), demonstrating
active afferent arteriolar responses to increases in renal perfusion
pressure in the absence of the AT1A receptor.
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Afferent arteriolar ANG II responses.
Baseline afferent arteriolar diameters were similar in kidneys from WT
(n = 11) and AT1A/
(n = 17) mice subjected to ANG II challenges, averaging 14.6 ± 0.4 and
15.2 ± 0.4 µm, respectively. Afferent arterioles from WT mice
vasoconstricted by 10 ± 1 (0.1 nM ANG II), 19 ± 2 (1 nM ANG
II), and 37 ± 5% of control values (10 nM ANG II) (Fig.
3). Afferent arteriolar reductions in
diameter were 7 ± 1, 14 ± 2, and 22 ± 2% of control
in response to 0.1, 1, and 10 nM ANG II, respectively, in vessels
obtained from AT1A
/
mice. The ANG II responses of
afferent arterioles from AT1A+/
mice (n = 4) were intermediate in magnitude relative to those of WT and
AT1A
/
mice. Baseline afferent arteriolar diameter in
AT1A+/
mice averaged 15.0 ± 1.3 µm and decreased
9 ± 1, 19 ± 4, and 34 ± 8% of control in response to
0.1, 1, and 10 nM ANG II, respectively. Therefore, 0.1, 1, and 10 nM
ANG II caused significant reductions in afferent arteriole diameters in
kidneys from WT, AT1A+/
, and AT1A
/
mice.
Afferent arteriole vasoconstrictor responses to low-dose ANG II (0.1, 1 nM) were similar for WT, AT1A+/
, and
AT1A
/
mice. This effect was not different among the
groups. ANG II (10 nM) reduced afferent arteriolar diameter by 37 ± 5 in WT, 34 ± 8 in AT1A+/
, and by only 22 ± 2% in AT1A
/
mice. Diameter responses to the highest
dose of ANG II were significantly reduced by 40% in kidneys from
AT1A
/
compared with WT mice. ANG II responses in
kidneys from AT1A+/
were not different in those from WT
or AT1A
/
mice.
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Afferent arteriolar ANG II time control responses.
This series of experiments was performed to demonstrate that afferent
arterioles respond to repeated application of increasing concentrations
of ANG II. Afferent arteriolar diameter in kidneys from
AT1A/
mice (n = 3) averaged 17.7 ± 0.1 µm at baseline. Application of 0.1, 1, and 10 nM ANG II
produced graded reductions in afferent arteriolar diameter of 6 ± 1, 15 ± 1, and 23 ± 1% of control levels, respectively
(Fig. 4). On the second application of
0.1, 1, and 10 nM ANG II, vessel diameters decreased 6 ± 1, 14 ± 1, and 19 ± 2% of control levels, respectively. The
afferent arteriolar responses to the first and second applications of
ANG II did not differ significantly. Afferent arteriolar diameters were
not significantly different between baseline and the two recovery
periods. These data provide evidence that mouse juxtamedullary afferent
arterioles do not display tachyphalaxis to ANG II at the concentrations
used and respond actively to a repeat application of the peptide under
these experimental conditions.
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Efferent arteriolar ANG II responses.
Efferent arteriole baseline diameters in kidneys from
AT1A/
mice were significantly larger than in those from
WT mice, averaging 19.6 ± 0.7 and 17.0 ± 0.3 µm,
respectively. Efferent arterioles of WT mice vasoconstricted in
response to 0.1, 1, and 10 nM ANG II by 6 ± 1, 11 ± 1, and
21 ± 5% of control (P < 0.05; Fig.
5). However, efferent arterioles from
AT1A
/
mice did not respond to ANG II. The
AT1-receptor antagonist candesartan alone did not alter
efferent arteriolar diameter (100% of control) of WT
(n = 6) or AT1A
/
(n = 6) mice. As shown in Fig. 5, blockade of the AT1 receptor
with candesartan completely prevented the efferent arteriolar
vasoconstrictor responses to ANG II in kidneys from WT mice.
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DISCUSSION |
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The AT1 receptor is primarily responsible for the vascular and tubular actions of the renal renin-angiotensin system. There are two unique AT1 receptor subtypes in rodents, AT1A and AT1B, which cannot be distinguished using pharmacological antagonists. Accordingly, it has not been possible to discriminate between renal microvascular AT1A and AT1B receptor subtype function. It is known that AT1A and AT1B receptor mRNAs are expressed on the afferent arteriole (2, 17). However, there is no information on the localization of AT1B receptor mRNA or protein on the efferent arteriole. Therefore, the purpose of the present study was to determine the functional contribution of the AT1A and AT1B receptors to the renal microvascular responses to changes in renal perfusion pressure and the segment-specific vasoconstrictor actions of ANG II.
The requirement for AT1A receptors for afferent arteriolar
vascular control mechanisms with regard to elevations in renal arterial
perfusion pressure were examined in the present study using
gene-targeted mice. Although AT1A
receptor-deficient mice have been shown to lack a tubuloglomerular
feedback mechanism (25), the present study revealed that
increases in renal perfusion pressure evoke indistinguishable afferent
arteriolar vasoconstrictor responses in WT and AT1A/
mouse kidneys. Significant reductions in afferent arteriolar diameter
were observed in WT, heterozygous, and homozygous
AT1A-disrupted mouse kidneys in response to stepwise increases in renal arterial pressure. The magnitude of the afferent arteriolar vasoconstriction in the mouse kidney was similar to the
responses seen previously in the rat, in which single afferent arteriolar blood flow was efficiently autoregulated over the same pressure range (27). Thus afferent arteriolar
autoregulatory responsiveness in the isolated perfused mouse kidney is
similar to that previously observed in the rat and does not appear to be altered by the loss of AT1A receptor function. The
maintenance of renal autoregulatory responsiveness in
AT1A
/
mice suggests a prominence of the myogenic
mechanism in these animals. Alternatively, tubuloglomerular feedback
responses may be active in the deep, juxtamedullary nephron population
of AT1A
/
mice and may reflect mediation by the
AT1B receptor.
The relative contributions of AT1A and AT1B
receptors to afferent arteriolar resting tone were evaluated in the
present study. Afferent arteriolar diameters were not significantly
different under baseline conditions (100 mmHg renal perfusion pressure, superfusion with vehicle solution) in kidneys from WT and
AT1A/
mice. The lack of a between-group difference in
baseline diameter indicates no effect of loss of AT1A
receptors on basal afferent arteriolar tone. In addition, basal
afferent arteriolar diameters were not altered after AT1
receptor blockade by candesartan in kidneys from WT or
AT1A
/
mice. This suggests that there is little influence of ANG II on basal afferent arteriolar tone under the conditions of the isolated blood-perfused mouse kidney preparation.
The relative contributions of AT1A and AT1B
receptors to afferent arteriolar responses to ANG II were determined in
kidneys from WT, AT1A+/ and AT1A
/
mice.
The afferent arteriolar diameter responses to ANG II in WT mice were
similar to those previously reported in the rats pretreated with
enalprilat (3, 9). Significant reductions in afferent
arteriolar diameters were observed over the concentration range of
0.1-10 nM in kidneys from WT, AT1A+/
, and
AT1A
/
mice. We attribute the ANG II vasoconstrictor responses in afferent arterioles from AT1A
/
mice to be
mediated by the AT1B receptor subtype. Surprisingly, the
magnitude of the afferent arteriolar responses in the three groups of
mice was similar at the 0.1 and 1 nM ANG II doses. This was unexpected based on previous studies, which demonstrated a negligible pressor response to bolus systemic ANG II (11) and diminished
renal blood flow response to bolus intrarenal administration of ANG II
(22) in kidneys from AT1A
/
mice compared
with controls. However, it has been shown that AT1A
/
mice have significantly enhanced renal renin mRNA expression
(19) and elevated plasma ANG II levels (6).
Elevated circulating ANG II may have contributed to the lack of ANG II
response in kidneys from AT1A
/
mice in the above
studies. Endogenous ANG II may occupy the AT1B receptors and limit accessability of exogenously administered ANG II. In fact,
after administration of an angiotensin-converting enzyme inhibitor,
both systemic pressor and renal blood flow responses to ANG II were
enhanced (6, 19). Therefore, suppression of the endogenous
production of ANG II may be necessary to reveal the function of the
AT1B receptor in the absence of the AT1A
receptor. It is possible that circulating ANG II levels are low using
the mouse juxtamedullary nephron technique, in which the kidney is perfused with blood obtained from a donor rat and, therefore, afferent
arteriolar responses in kidneys from AT1A
/
mice are revealed.
In contrast to the afferent arteriolar vasoconstrictor responses to
low-dose ANG II, afferent arteriolar diameter responses to the high
dose of ANG II, 10 nM, were significantly different in kidneys from WT
and AT1A/
mice. Afferent arteriolar diameter responses
for the AT1A
/
mice were only 60% of the magnitude of
the response for WT mice. The difference in the magnitude of the
response may be due to the maximal vasoconstrictor contribution of the
AT1B receptors. The vasoconstrictor responses to ANG II were completely inhibited by the AT1 receptor blocker
candesartan. This drug blocks both the AT1A and
AT1B receptor subtypes, similar to the properties of
losartan (15). Therefore, the vasoconstrictor effects of
ANG II on the afferent arteriole are mediated by the AT1
receptor for both WT and AT1A
/
mice. There was no
evidence of AT2 receptor-mediated vasodilation in the
presence of AT1 receptor blockade and ANG II in the present
study. We conclude that for WT mice, afferent arteriolar responses are
mediated by both the AT1A and AT1B receptors,
whereas for AT1A
/
mice, this effect is mediated
exclusively by the AT1B receptors. In addition, in the
absence of AT1A receptors, 10 nM ANG II evokes an
attenuated, candesartan-sensitive, afferent arteriolar constriction in
kidneys from AT1A
/
mice, implicating activation of
AT1B receptors. It is not known at the present time whether
AT2 and/or AT1B receptor protein expression is
altered in afferent arterioles of AT1A
/
mice.
The relative contributions of AT1A and AT1B
receptors to efferent arteriolar responses to ANG II were determined in
kidneys from WT and AT1A/
mice. Efferent arterioles of
WT mice responded in a dose-dependent manner to ANG II, similar to
juxtamedullary efferent arterioles of the rat (3, 9).
However, efferent arterioles of AT1A
/
mice did not
respond to ANG II. These data suggest that AT1A receptors
are primarily responsible for ANG II-induced efferent arteriolar
vasoconstriction. The lack of ANG II responses in efferent arterioles
of AT1A
/
mice suggests that AT1B receptors
are not functionally expressed on the efferent arteriole.
In contrast to the similarities in the afferent arteriolar resting
diameters of WT and AT1A/
mice, efferent arteriolar
diameters of AT1A
/
mice were significantly larger than
for WT mice. Such increased efferent arteriolar diameter combined with
an increased glomerular ultrafiltration coefficient, resulting from
reduced ANG II-dependent activation of AT1A receptors, may
contribute to the maintenance of renal plasma flow and glomerular
filtration rate in the normal range in hypotensive
AT1A
/
mice (6). However, there may be
limitations to our ability to extrapolate our data obtained from in
vitro studies to an in vivo setting. It is not likely that the larger
resting efferent arteriolar diameter in kidneys from
AT1A
/
mice is a result of the direct loss of the effects of endogenous ANG II on the AT1A receptor because
resting diameter was not influenced by candesartan. At this time, we
can only speculate on the potential interaction of ANG II-induced vasoconstriction and other vasodilatory mechanisms at the site of the
efferent arteriole. The larger resting efferent arteriolar diameter of
AT1A
/
mice may reflect a lack of compensation by the
vasoconstrictor properties of the AT1A receptor. It has
been shown that AT1A
/
mice have increased expression
and activity of neuronal nitric oxide synthase (14).
Because nitric oxide derived from neuronal nitric oxide synthase
localized in the macula densa cells and efferent arterioles
(1) has been shown to play an important role in renal
hemodynamics, it is possible that nitric oxide has profound effects on
the resting tone of the efferent arteriole lacking AT1 receptors.
In conclusion, afferent arteriolar autoregulatory capability is not
affected by the absence of AT1A receptors. This study in
AT1A/
mice provides functional evidence of distinct
distribution patterns for AT1 receptor subtypes within the
renal microvasculature. We conclude that afferent arteriolar
vasoconstrictor responses to ANG II are mediated by AT1A
and AT1B receptors, whereas efferent arteriole
vasoconstrictor responses to ANG II are mediated by only
AT1A receptors in the mouse kidney.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Pamela K. Carmines and L. Gabriel Navar for a critical review of the manuscript and Camie Snow for performing the Southern blot analysis. Dr. Peter Morsing of Astra Hassle, Gothenburg, Sweden, generously provided the AT1 receptor antagonist candesartan (Atacand) utilized for these studies.
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FOOTNOTES |
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This work was supported by American Heart Association Scientist Development Grant 9930120N and National Institutes of Health Grants DK-62003-01 (to L. M. Harrison-Bernard) and HL-26371.
Present address of A. K. Cook: Dept. of Physiology, Medical College of Georgia, 1120 15th St., Augusta, GA 30912-3000.
Address for reprint requests and other correspondence: L. M. Harrison-Bernard, Dept. of Physiology, SL39, Tulane Univ. Health Sciences Center, 430 Tulane Ave., New Orleans, LA 70112-2699 (E-mail: lharris{at}tulane.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 November 12, 2002;10.1152/ajprenal.00340.2002
Received 19 September 2002; accepted in final form 12 November 2002.
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