(Hypertension. 1999;33:524-529.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
1- and 2-Adrenoceptor Control of Sodium Transport Reverses in Developing Hypertension
From the Pharmacology Department, Dartmouth Medical School, Hanover, NH.
Correspondence to Dr Frank A. Gesek, Pharmacology Department, Dartmouth Medical School, 7650 Remsen, Room 611, Hanover, NH 03755. E-mail fg{at}dartmouth.edu
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Abstract |
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Abstract—
-Adrenergic receptor
(AR) activation enhances sodium retention in certain forms of
hypertension. The objective of the present study was to understand
the role of -ARs in regulating sodium transport by distal tubules
(DT). DT cells were isolated from kidneys of spontaneously hypertensive
rats (SHR) and Wistar-Kyoto (WKY) rats at 6 weeks, when hypertension is
developing, or at 12 weeks, when hypertension is established. The
1-AR agonist phenylephrine increased
22Na uptake by 50% into DT cells of 6-week SHR; no effect
was observed with WKY cells. The 2-AR agonist B-HT 933
increased uptake by only 10%. At 12 weeks, the pattern of -AR
regulation was reversed: 1-AR–induced sodium uptake was
only 15%, whereas 2-AR activation increased sodium
uptake by 35% in SHR and WKY cells. 1-AR–induced
sodium uptake in 6-week SHR cells was abolished by prazosin;
2-AR–stimulated sodium uptake was blocked by yohimbine
in 12-week SHR and WKY. Competitive binding studies were performed with
[3H]prazosin and 1A-, 1B-,
and 1D-selective antagonists with DT cell
membranes from 6- and 12-week SHR and WKY. 2-AR subtypes
were determined with [3H]rauwolscine and
2A- and 2B-selective
antagonists. Expression of 1B-ARs was
increased 4-fold in DT cells during the developing phase of
hypertension in SHR. No change was detected in 2-AR
expression. DT cells transiently increase
[Ca2+]i in response to 1-AR
agonists from 6-week but not 12-week SHR. Conversely,
2-AR agonists increase [Ca2+]i
at 12 weeks. In summary, during developing hypertension,
1-ARs increase sodium uptake and
[Ca2+]i in SHR cells. Expression of
1B-ARs is selectively upregulated during developing
hypertension. In established hypertension (and normotension),
2-ARs regulate sodium transport and
[Ca2+]i in DT cells. We conclude that a
molecular switch of 1-AR and 2-AR
signaling occurs in DT cells during the development of
hypertension.
Key Words: receptors, adrenergic • blood pressure • catecholamines • epinephrine • hypertension • calcium • norepinephrine
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Introduction |
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One proposal for the initiation and maintenance of hypertension centers on a reduced capacity of the kidneys to excrete salt and water in proper relation to intake.1 Sodium retention could initiate or contribute to the development of hypertension by activating mechanisms in vascular smooth muscle, the sympathetic nervous system, or expansion of effective extracellular fluid or plasma volume.2 3 Chronic stimulation of renal nerves or intrarenal infusion of norepinephrine increases sodium retention and is capable of producing hypertension.4 5 Conversely, renal denervation attenuates sodium retention and the onset of hypertension6 7 but exerts only minimal effects in adult animals with established hypertension.7 8
Metabolic balance studies examining the intake and excretion of sodium and water document that spontaneously hypertensive rats (SHR) between 4 to 7 weeks of age retain more sodium than do age-matched Wistar-Kyoto (WKY) rats.2 During this period, urinary excretion was less in SHR than WKY rats and attributed to renal mechanisms. As the animals matured and systolic arterial pressure increased, renal sodium excretion was normalized in 8- to 13-week SHR.9 These findings suggest that altered regulation of renal sodium absorption parallels the increase in pressure observed in SHR.
The focus of this study was to test the hypothesis that -adrenergic
receptors (-ARs) contribute to the increased sodium absorption in
distal tubule (DT) cells of SHR during developing hypertension (4 to 7
weeks). Renal nerves impinge directly on proximal tubules (PT) and
DT.10 Previous studies showed that
1- and 2-AR agonists
stimulate Na+/H+ exchange
to a similar level in PT cells from SHR and WKY rats from 4 to 16 weeks
of age.11 It is predicted that -ARs increase sodium
absorption in DT cells. The mammalian DT is composed of 3 segments:
distal convoluted tubule, connecting tubules, and initial
cortical collecting duct.12 In aggregate, these segments
critically regulate the absorption of up to 15% of the filtered sodium
load.13 Activation of -ARs on DT segments may
significantly increase sodium retention during the developing phase of
hypertension in SHR. The enhanced sodium retention observed during this
phase may be due to increased expression of receptor subtypes or
alternative receptor signaling.
It is proposed that a reversal of 1- and
2-AR regulation occurs during the developing
and established hypertension. During the phase of increasing blood
pressure in SHR, 1-ARs increase sodium
transport in DT cells. The increase in
1-AR–stimulated sodium uptake correlates with
increased 1B-AR binding on DT cells during
developing hypertension. In established hypertension in SHR and in
normotensive WKY rats, 2-ARs, but not
1-ARs, increase sodium transport. These
observations indicate increases in specific
1-AR subtypes enhance sodium transport in DT
cells during developing hypertension and 2-ARs
regulate sodium absorption in DT cells during established hypertension
and normotension.
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Methods |
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Preparation of Freshly Isolated and Primary Cultures of Tubule Cells From SHR and WKY Rats
Salt-insensitive SHR and WKY rats of 6 and 12 weeks of age were obtained (Taconic) and maintained on normal rat chow and water ad libitum. The weights of 6- and 12-week-old SHR were similar to those of WKY rats. Systolic blood pressures were measured in awake animals as previously reported.11 The blood pressures of 6-week-old SHR averaged 139 mm Hg compared with 106 mm Hg in 6-week-old WKY rats (P<0.05). Blood pressures of 12-week-old SHR averaged 175 mm Hg, significantly greater than those observed with WKY rats (110 mm Hg), and agree with our previous observations11 and those of others14 15 that correspond to developing hypertension and established hypertension phases. DT and PT cells were prepared from age-matched SHR and WKY rats of 6 weeks (developing hypertension) and 12 weeks (established hypertension)16 with isolation of DT cells using a double-antibody isolation technique.17 Primary cultures of DT and PT cells were prepared from freshly isolated cells.18
Isotopic Sodium Uptake Measurements
A rapid filtration technique described in previous
reports19 was used to measure uptake of
22Na into DCT cells. Briefly, WKY and SHR cells
were placed in a sodium-containing buffer, with or without
1- or 2-AR agonists
or antagonists for 1 minute before the addition and
vortexing of 1 aliquot of 22Na (Amersham) to
initiate isotope uptake. In all experiments reported, tracer uptake was
terminated after 1 minute by the rapid addition of ice-cold isosmotic
Li2SO4-HEPES rinse buffer
and filtered onto Whatman GF/C filters using a Millipore 12-port
manifold.
Receptor Binding Assays
Saturation binding experiments were performed using
[3H]prazosin and
[3H]rauwolscine (New England Nuclear) for
1- and 2-ARs,
respectively. Concentrations ranging from 0.01 to 5 nmol/L labeled
ligand with 100 µg SHR and WKY cell membrane protein were used per
reaction tube. Nonspecific binding was assessed with 10 µmol/L
phentolamine or yohimbine.20 21 Membrane binding
of [3H]prazosin or
[3H]rauwolscine was performed at 37°C for 30
minutes, and incubations were terminated by ice-cold buffer addition
and rapid filtration. Specific binding was defined as total binding
minus nonspecific binding; nonspecific binding averaged ~21% of
total binding. Low concentrations (10 nmol/L) of the subtype-selective
receptor antagonists WB4101 (1A),
spiperone (1B), and BMY7378
(1D) were used to define the relative
proportions of 1-AR subtypes with
[3H]prazosin binding to SHR and WKY DT and PT
cell membranes.22 For determining the relative proportions
of 2A- and 2B-ARs in
SHR and WKY DT and PT cell membranes, oxymetazoline
(2A selective) and ARC239
(2B selective) were used.23
Binding constants (Bmax,
Kd) were calculated using nonlinear
regression analysis with Prism software (GraphPAD
Software).
Measurement of [Ca2 ]i
Intracellular fluorescence measurements of calcium were
performed as previously described in detail.24 Primary
cultures of SHR and WKY DT and PT cells were grown to near-confluence
on 25-mm glass coverslips and incubated for 60 minutes at 37°C with
Fura-2 AM (10-5 mol/L; Molecular Probes).
Fluorescence excitation and emission intensity were measured
with a Nikon Photoscan-2.
Materials and Preparation of Drug Solutions
-AR agonists and antagonists were prepared so
that the molar concentration indicated in the text is the final
concentration to which cells were exposed. Solutions containing drugs
were prepared fresh daily. Rolipram was purchased from BIOMOL Research
Laboratories; B-HT 933 was a gift from Boehringer-Ingelheim
Pharmaceuticals. Other adrenergic agonists and antagonists
were purchased from Research Biochemical International.
Statistical Evaluation of Data
All [3H]prazosin and
[3H]rauwolscine binding and
22Na uptake measurements were made in triplicate
within individual experiments. The data are presented as
mean±SEM, where n indicates the number of separate experiments.
Comparisons between control and drug-treated groups were examined by
posthoc analysis of multiple comparisons with the Bonferroni or
Newman-Keuls multiple comparisons test using the statistical software
Instat for MacIntosh (GraphPAD Software). Values of P
0.05
were considered significant.
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Results |
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-AR Effects on Sodium UptakeThe responses of DT cells to equimolar concentrations of the
1-selective agonist phenylephrine
(PHE), the 2-selective agonist B-HT 933, and
the endogenous mixed norepinephrine (NE) are
depicted in Figure 1
. The basal (control)
rates of uptake were similar among SHR and WKY rats at both 6- and
12-week time points. Only DT cells from 6-week SHR increased sodium
uptake when treated with PHE. There was no effect when 6-week WKY DT
cells were treated with PHE. By comparison, DT cells from 6-week SHR
exhibited no response to the 2-AR agonist B-HT
933. DT cells from 6-week WKY rats increase sodium uptake in response
to the 2-AR agonist. Both 12-week SHR and WKY
DT cells treated with B-HT 933 exhibit significantly increased rates of
sodium uptake. The mixed 1- and
2-AR agonist NE increases sodium uptake in DT
cells from SHR and WKY; this presumably is due to the
1-AR stimulation in SHR DT cells at 6 weeks
and 2-AR stimulation that occurs in WKY and
12-week SHR DT cells.
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Specific 1- and
2-AR antagonism of the NE response in 6-
and 12-week SHR DT cells provides further evidence of the shift from
1-AR regulation during developing hypertension
and 2-AR regulation during established
hypertension. As depicted in Figure 2, NE-stimulated sodium uptake into 6-week SHR DT cells is abolished by
pretreatment with prazosin, an 1-AR
antagonist. At 12 weeks, NE-stimulated sodium uptake into
SHR DT cells is blocked by the 2-AR
antagonist yohimbine. When 6- and 12-week WKY DT cells were
stimulated with NE, sodium uptake was blocked only by yohimbine.
Pretreatment of 6- or 12-week WKY DT cells with prazosin had no
demonstrable effect on NE-stimulated sodium uptake.
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Expression of -AR Subtype Protein in Developing and
Established Hypertension
To discern the subtypes of
1- and
2-ARs expressed in SHR and WKY DT cells, receptor
protein was measured using [3H]prazosin and
[3H]rauwolscine in competitive binding
experiments. Specific high affinity binding for both
1- and 2-ARs was
detected in DT and PT membranes from SHR and WKY. Specific binding
averaged 73% to 90% in all saturation binding experiments. The mean
1-AR density in 6-week SHR DT membranes was
250±26 fmol/mg protein and was significantly greater than that of
6-week WKY DT membranes (84±11 fmol/mg protein). The
1-AR density of 12-week SHR DT membranes was
113±16 fmol/mg protein and comparable to the value detected for
12-week WKY DT membranes (92±14 fmol/mg protein). As depicted in
Figure 4, there is significantly greater
1B-AR binding with 6-week SHR DT membranes
than with those of 12-week SHR or WKY DT membranes. The significant
increase in total 1-AR density of a 6-week SHR
DT membranes is in large part attributable to the increased expression
of the 1B-AR subtype. Compared with expression
of 1B-ARs in 12-week SHR and WKY DT cells,
there is nearly 4-fold greater expression of this subtype in 6-week SHR
DT cells. Expression of 1A-AR subtypes was
comparable in SHR and WKY 6- and 12-week DT membranes. Although message
for 1D-AR was detected by RT-PCR, competitive
binding studies indicate <6% of the total binding in DT membranes
from SHR and WKY rats was attributable to this particular subtype.
Conflicting results relating to the expression of the
1D-AR subtype indicate the absence of this
subtype in kidney cortex,25 26 whereas
1D-AR mRNA is present in DT cells;
protein expression of this subtype is very low in DT cells.
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To determine whether protein expression of
1-ARs is increased in other tubule segments,
we measured 1-AR binding in PT membranes from
6- and 12-week SHR and WKY rats (Figure 5). The increased
expression of the 1B-AR subtype is specific
for DT membranes from 6-week SHR. The 1B- and
1A-AR subtype expression is not increased in
PT membranes from SHR or WKY membranes at 6 or 12 weeks. Again,
consistent with other reports,25 26
1A- and 1B-AR
subtypes comprise 
50% each of the 1-ARs
expressed on the PT. Expression of the 1D-AR
averaged <7% of the total 1-AR binding in
WKY and SHR PT membranes.
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We theorized that with a reduction in 1-AR
expression at 12 weeks in SHR DT cells, there may be an accompanying
increase in expression of a particular 2-AR
subtype. To test this theory, competitive binding studies were
performed with DT membranes from SHR and WKY rats of 6 and 12 weeks and
summarized in Figure 6. Similar levels of
2-AR binding were observed in DT and PT cell
membranes from 6- and 12-week SHR and WKY. Total specific binding of
2-ARs was 93 fmol/mg protein in membranes from
6-week SHR compared with 84 fmol/mg protein in WKY.
2A-AR binding was 61 versus 47 fmol/mg protein
in SHR compared with WKY, whereas 2B-AR
binding was 44 versus 36 fmol/mg protein in SHR compared with WKY. With
membranes from 12-week SHR, total specific binding was 106 versus 97
fmol/mg protein in SHR compared with WKY, respectively.
2A-AR binding was 68 fmol/mg protein compared
with 57 fmol/mg protein in WKY. 2B-AR binding
was ~50 fmol/mg protein for both SHR and WKY with membrane from
12-week DT cells. An equal ratio of
2A/2B sites in PT and
DT membranes from SHR and WKY was consistent with densities
reported by others.25 26 Although 6-week SHR express
significantly greater numbers of 1B-ARs during
developing hypertension, the densities of
2-ARs remain constant during developing and
established hypertension.
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Signaling of 1- and 2-ARs During
Developing and Established Hypertension
The 1- and 2-ARs
activate a number of signaling pathways, including
phosphoinositide-sensitive phospholipase C (PI-PLC),
phospholipase D (PLD), phosphatidylcholine-sensitive PLC (PC-PLC),
phospholipase A2
(PLA2),27 28 and
mitogen-activated protein kinase (MAPK).27 29
Studies with PT and MDCK cells demonstrate
1-ARs activate PI-PLC and lead to
formation of IP3 and diacylglycerol, transient
increases in intracellular Ca2+
([Ca2+]i, and subsequent
activation of PKC.27 28 30 2-ARs
couple to pertussis toxin–sensitive Gi proteins
in PT to inhibit adenylyl cyclase31 but couple to PI-PLC
in DT cells.24 To examine the signal pathways
activated by 1- and
2-ARs during developing and established
hypertension, we measured agonist-induced increases of
[Ca2+]i in DT cells of
SHR and WKY rats with the fluorescent dye, Fura-2 AM. A
representative experiment is depicted in Figure 6
. After measurement of resting levels of
[Ca2+]i in DT cells from
6-week SHR or WKY, cells were treated with the
1-agonist PHE. SHR DT cells responded with a
prompt and significant increase in
[Ca2+]i from a basal
level of 107 nmol/L to 248 nmol/L, whereas WKY DT cells displayed
negligible changes in
[Ca2+]i (basal level of
103 nmol/L versus 112 nmol/L with PHE). When cells were treated with
the selective 2-agonist B-HT 933, there was an
increase in WKY DT cells (control level of 102±6 nmol/L versus 266±9
nmol/L with B-HT 933) and no response in the SHR DT cells (basal level
of 114±5 nmol/L compared with 128±6 nmol/L with B-HT 933). We next
sought to determine whether the 1- and
2-AR response was different at 12 weeks
between SHR and WKY DT cells given the reduction in
1B-AR expression. DT cells from 12-week SHR
increase [Ca2+]i in
response to B-HT 933 from 109±3 to 249±8 nmol/L. A similar increase
was observed in DT cells from 12-week WKY rats (control level of 111±5
nmol/L and 249±8 nmol/L with B-HT 933 treatment. By comparison, PHE
did not significantly increase
[Ca2+]i in DT cells from
12-week SHR or WKY rats (control levels of 112 and 106 nmol/L and PHE
levels of 121 and 117 nmol/L for SHR and WKY, respectively). The
1-AR–stimulated increase of
[Ca2+]i observed with
6-week SHR DT cells is absent in DT cells from 12-week SHR. In
contrast, DT cells of 12-week SHR and WKY rats displayed similar
increases to an 2-agonist. These findings
suggest that 1B-ARs mediate the increase of
[Ca2+]i in 6-week SHR DT
cells and that 2-ARs assume this function
during established hypertension in SHR or in normotensive WKY DT
cells.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The objective of this study was to determine the role of
-ARs
in the development of hypertension. We propose that renal
1-ARs are important in the initiation and
development of hypertension because they significantly increase sodium
absorption in the DT, a segment that critically regulates 10% to 15%
of final sodium excretion. As hypertension progresses,
1-AR expression is downregulated and
2-ARs regulate sodium absorption in DT
cells.
Renal nerve stimulation reduces sodium excretion.5
This effect is abolished by 1-AR
antagonists.32 In rats chronically treated
with prazosin, an 2-AR antagonist
is required to fully abolish the increase in sodium
retention.32 These findings suggest both
1- and 2-AR receptors
regulate sodium absorption. In PT cells, 1-
and 2-ARs exert synergistic effects on
Na+/H+
exchange.33 However, 1- and
2-AR–stimulated
Na+/H+ exchange is similar
in WKY and SHR PT cells during developing and established
hypertension.11 These findings support the view that
-AR regulation of sodium absorption is not altered in PT cells
during developing hypertension.
Numerous studies indicate 1-ARs enhance sodium
retention.5 34 35 SHR excrete significantly less sodium
during the onset of hypertension (weeks 4 to 7).36 As
hypertension progresses, the tendency to retain sodium is reversed
until levels approximate those of normotensives during weeks 10 to 13.
Our results with -AR stimulation of sodium uptake are
consistent with these observations.
We observe significant differences in 1-
and 2-AR regulation of sodium absorption in DT
cells during developing and established hypertension. As depicted in
Figure 1, the selective 1-AR agonist
PHE significantly increases sodium uptake into DT cells during
developing hypertension in SHR but has no effect in age-matched WKY. By
comparison, an 2-AR agonist increases sodium
uptake in WKY, but not SHR, DT cells. At 12 weeks, both SHR and WKY
increase sodium uptake in response to 2- but
not 1-AR agonists. The increased uptake of
sodium in SHR DT cells during developing hypertension coincides with
high levels of the 1B-AR subtype protein
expressed at this phase (Figure 4). Once hypertension is
established, the density of the 1B-ARs in SHR
DT cells is similar to that observed in WKY. Finally, the signaling
through increased [Ca2+]i
also correlates with enhanced 1B-AR expression
and sodium uptake during this phase. Once expression of the
1B-ARs is reduced during established
hypertension, 1-AR subtypes no longer signal
increases in [Ca2+]i in
DT cells. Although speculative, 2-ARs may
regulate final changes in sodium absorption through activation and
signaling of the PI-PLC pathway in DT cells. Because this pathway is
present in 6-week WKY rats and these animals do not exhibit
increased blood pressure, the 2-ARs may
modulate physiological changes in sodium
absorption.
Although the exact mechanisms underlying the upregulation of
renal -ARs in SHR remain unclear, the increased density may
represent a genetic abnormality.37 Two lines of
evidence support this theory: (1) increased receptor density in SHR
occurs before onset of the development of hypertension, and (2)
nongenetic models of hypertension do not exhibit increased receptor
expression. Several studies show that renal
2-AR receptor density is increased in
hypertension.37 38 39 Sanchez et al40 suggests
that 1-ARs increase during the developing
hypertension but that 2-ARs density is greater
during established hypertension. The data in Figure 4 are
consistent with reports that 1-ARs
increase during developing hypertension. By comparison, our data do not
indicate upregulation of 2-ARs during
developing or established hypertension. Intengan and
Smyth41 suggest a defective modulation of solute excretion
in 8-week SHR due to the 2A/D-AR. This defect
is not present in acquired models of hypertension. Our results
would be consistent with these observations because
2-ARs in DT cells do not signal an increase in
[Ca2+]i during developing
hypertension. During established hypertension and in normotensive
animals, the subtype of 2-ARs that modulates
sodium transport possesses the ability to signal through PI-PLC
pathways.24 Altered renal sodium balance in SHR may
represent a consequence of enhanced
1-AR–stimulated retention and lack of
2-AR–induced clearance during the developing
phase of hypertension.
In summary, we demonstrate that -ARs stimulate sodium uptake in DT
cells. During developing hypertension in SHR, the expression of
1B-AR protein correlates with a significant
increase in sodium uptake from 1-AR
stimulation. In age-matched normotensive WKY DT cells,
2-ARs are capable of increasing sodium uptake.
During established hypertension, the expression of
1B-ARs is reduced and
1-ARs no longer stimulate sodium uptake. In DT
cells from SHR with established hypertension and normotensive WKY rats,
regulation of sodium transport is mediated by
2-ARs. Transient increases in
[Ca2+]i occur with
1-ARs during developing hypertension but
switch to 2-ARs during established
hypertension. The switch in receptor expression and signaling does not
occur in PT cells. We propose that the enhancement of
1-AR expression that occurs during developing
hypertension contributes to the initiation of hypertension, whereas
during established hypertension or in normotensive animals,
2-ARs modulate sodium transport in DT
cells.
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Acknowledgments |
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This study was supported by National Institutes of Health Grant DK-46064. I would like to acknowledge the technical assistance of Bonita A. Coutermarsh and Fengming Liu.
Received September 17, 1998; first decision October 16, 1998; accepted October 28, 1998.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Guyton AC, Coleman TG, Cowley AV Jr, Scheel KW, Manning RD Jr, Norman RA Jr. Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med. 1972;52:584–594.[Medline] [Order article via Infotrieve]
2. Janssen BJA, Smits JFM. Renal nerves in hypertension. Miner Electrolyte Metab. 1989;15:74–82.[Medline] [Order article via Infotrieve]
3. Tobian L. Introduction to the symposium: the sympathetic nervous system really is a key element in hypertension, with treatment implications. Am J Hypertens. 1996;9:111S–112S.[Medline] [Order article via Infotrieve]
4. Osborn JL, Roman RJ, Harland RW. Mechanisms of antinatriuresis during low-frequency renal nerve stimulation in anesthetized dogs. Am J Physiol. 1985;249:R360–R367.
5.
Osborn JL, Holdaas H, Thames MD, Dibona GF. Renal
adrenoceptor mediation of antinatriuretic and renin
secretion responses to low frequency nerve stimulation in the dog.
Circ Res. 1983;53:298–305.
6.
Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger
JP. Renal denervation attenuates the sodium retention and hypertension
associated with obesity. Hypertension. 1995;25:893–897.
7.
Yoshida M, Satoh S. Role of renal nerves on pressure
natriuresis in spontaneously hypertensive rats. Am J
Physiol. 1991;260:F81–F85.
8. Kassab S, Kato T, Wilkins FC, Mizelle L, Granger JP. Role of renal nerves in mediating the blunted natriuretic response to acute saline load in obese dogs. Am J Hypertens. 1997;10:315–322.[Medline] [Order article via Infotrieve]
9.
Wang RX, Limbird LE. Distribution of mRNA
encoding three 2-adrenergic receptor subtypes
in the developing mouse embryo suggests a role for the
2A subtype in apoptosis. Mol
Pharmacol. 1997;52:1071–1080.
10.
Barajas L, Powers K, Wang P. Innervation of the renal
cortical tubules: a quantitative study. Am J Physiol. 1984;247:F50–F60.
11.
Gesek FA, Schoolwerth AC. Hormone responses of
proximal Na+-H+ exchanger
in spontaneously hypertensive rats. Am J Physiol. 1991;261:F526–F536.
12.
Madsen KM, Tisher CC. Structural-functional
relationships along the distal nephron. Am J Physiol. 1986;250:F1–F15.
13. Ellison DH, Velazquez H, Wright FS. Thiazide-sensitive sodium chloride cotransport in early distal tubule. Am J Physiol. 1987;2536:F546–F554.
14.
Brazy PC, Klotman PE. Increased oxidative
metabolism in renal tubules from spontaneously hypertensive
rats. Am J Physiol. 1989;257:F818–F825.
15. Morduchowicz GA, Sheikh-Hamad D, Jo OK, Nord EP, Lee DBN, Yanagawa N. Increased Na+/H+ antiport activity in the renal brush border membrane of SHR. Kidney Int. 1989;36:576–581.[Medline] [Order article via Infotrieve]
16.
Gesek FA, Wolff DW, Strandhoy JW. Improved separation
of rat proximal and distal renal tubules. Am J Physiol. 1987;253:F358–F365.
17. Pizzonia JH, Gesek FA, Kennedy SM, Coutermarsh BA, Backsai BJ, Friedman PA. Immunomagnetic separation, primary culture and characterization of cortical thick ascending limb plus distal convoluted tubule cells from mouse kidney. In Vitro Cell Dev Biol 1990;27A:409–416.
18.
Stanton BA. Electroneutral NaCl transport by distal
tubule: evidence for
Na+/H+-Cl-/HCO3-
exchange. Am J Physiol. 1988;254:F80–F86.
19.
Gesek FA. Stimulation of
2-adrenergic receptors increases
Na+-K+-ATPase activity in
distal convoluted tubules. Am J Physiol. 1993;265:F561–F568.
20.
Moriyama N, Kurimoto S, Inagaki O, Takanashi M, Hamada
K, Kawabe K. Renal aging change of
1-adrenoceptor in Wistar rats. Gen
Pharmacol. 1995;26:347–351.[Medline]
[Order article via Infotrieve]
21.
Liu F, Nesbitt T, Drezner MK, Friedman PA, Gesek FA.
Proximal nephron Na+/H+
exchange is regulated by 1A- and
1B- adrenergic receptor subtypes. Mol
Pharmacol. 1997;52:1010–1018.
22.
Hancock AA. 1 Adrenoceptor
subtypes: a synopsis of their pharmacology and molecular biology.
Drug Dev Res. 1996;39:54–107.
23. Uhlén S, Wikberg JES. Delineation of three pharmacological subtypes of a2-adrenoceptor in the rat kidney. Br J Pharmacol. 1991;104:657–664.[Medline] [Order article via Infotrieve]
24.
Gesek FA. 2-Adrenergic
receptors activate phospholipase C in renal epithelial cells.
Mol Pharmacol. 1996;50:407–414.[Abstract]
25.
Feng F, Pettinger WA, Abel PW, Jeffries WB. Regional
distribution of 1-adrenoceptor subtypes in rat
kidney. J Pharmacol Exp Ther. 1991;258:263–268.
26.
Gopalakrishnan SM, Chen C, Lokhandwala MF.
Identification of 1-adrenoceptor subtypes in
rat renal proximal tubules. Eur J Pharmacol. 1993;250:469–472.[Medline]
[Order article via Infotrieve]
27. Xing M, Insel PA. Protein kinase C-dependent activation of cytosolic phospholipase A2 and mitogen-activated protein kinase by alpha1-adrenergic receptors in Madin-Darby canine kidney cells. J Clin Invest. 1996;97:1302–1310.[Medline] [Order article via Infotrieve]
28. Insel PA, Weiss BA, Slivka SR, Howard MJ, Waite JJ, Godson CA. Regulation of phospholipase A2 by receptors in MDCK-Dl cells. Biochem Soc Transm. 1991;19:329–333.[Medline] [Order article via Infotrieve]
29.
Wenham D, Rahmatullah RJ, Rahmatullah M, Hansen CA,
Robishaw JD. Differential coupling of
1-adrenoreceptor subtypes to
phospholipase C and mitogen activated protein kinase in
neonatal rat cardiac myocytes. Eur J Pharmacol. 1997;339:77–86.[Medline]
[Order article via Infotrieve]
30. Goligorsky MS, Hruska KA, Loftus DJ, Elson EL. Alpha1-adrenergic stimulation and cytoplasmic free calcium concentration in cultured renal proximal tubular cells: evidence for compartmentalization of Quin-2 and Fura-2. J Cell Physiol. 1986;128:466–474.[Medline] [Order article via Infotrieve]
31.
Strandhoy JW, Gesek FA. Stimulatory and
inhibitory interactions between -adrenoceptors and
the renal Na+/H+
antiporter. Kidney Int. 1989;35:488A. Abstract.
32.
Smyth DD, Umemura S, Pettinger WA. Renal
2-adrenergic receptors multiply and mediate
sodium retention after prazosin treatment. Hypertension. 1986;8:323–331.
33.
Gesek FA, Cragoe EJ Jr, Strandhoy JW. Synergistic
alpha-1 and alpha-2 adrenergic stimulation of rat
proximal nephron Na+/H+
exchange. J Pharmacol Exp Ther. 1990;249:694–700.
34.
Sattar MA, Johns EJ.
1-Adrenoceptor subtypes mediating
antinatriuresis in Wistar and stroke-prone spontaneously hypertensive
rats. Eur J Pharmacol. 1995;294:727–736.[Medline]
[Order article via Infotrieve]
35.
Elhawary AM, Pang CCY.
1B-Adrenoceptors mediate renal tubular sodium
and water reabsorption in the rat. Br J Pharmacol. 1994;111:819–824.[Medline]
[Order article via Infotrieve]
36.
Beierwaltes WH, Arendshorst WJ, Klemmer PJ.
Electrolyte and water balance in young spontaneously hypertensive rats.
Hypertension. 1982;4:908–915.
37. Takata Y, Kato H. Adrenoceptors in SHR: alterations in binding characteristics and intracellular signal transduction pathways. Life Sci. 1995;58:91–106.
38.
Graham RM, Pettinger WA, Sagalowsky A, Brabson J,
Gandler T. Renal alpha-adrenergic receptor abnormality in the
spontaneously hypertensive rat. Hypertension. 1982;4:881–887.
39.
Pettinger WA, Sanchez A, Saavedra J, Haywood JR,
Gandler T, Rodes T. Altered renal
alpha2-adrenergic receptor regulation in
genetically hypertensive rats. Hypertension. 1982;4:188–192.
40.
Sanchez A, Vidal MJ, Martinez-Sierra R, Saiz J.
Ontogeny of renal alpha-1 and alpha-2
adrenoceptors in the spontaneously hypertensive rat. J
Pharmacol Exp Ther. 1986;237:972–979.
41.
Intengan HD, Smyth DD. Renal
2a/d-adrenoceptor subtype function: Wistar as
compared to spontaneously hypertensive rats. Br J
Pharmacol. 1997;121:861–866.[Medline]
[Order article via Infotrieve]
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