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Departments of 1 Pediatrics, 2 Physiology and Biophysics, and 4 Medicine, Georgetown University Medical Center, Washington, District of Columbia 20007; and 3 Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan 48109
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To
determine if the defective interactions among D1-like
receptors, G proteins, and Na+/H+ exchanger 3 (NHE3) are consequences of hypertension, we studied these interactions
in rats, before (2-3 wk) and after (12 wk) the establishment of
hypertension. To eliminate the confounding influence of second
messenger action on D1 receptor-NHE3 interaction, studies
were performed in renal brush-border membranes (BBM) devoid of
cytoplasmic second messengers. NHE3 activity increased with age in
Wistar-Kyoto (WKY) rats (3 wk = 1.48 ± 0.39, n = 13; 12 wk = 2.83 ± 0.15, n = 16, P < 0.05) but not in
spontaneously hypertensive rats (SHRs; 3 wk = 2.52 ± 0.37, n = 11; 12 wk = 2.81 ± 0.20, n = 16). D1 receptor protein tended to
decrease, whereas NHE3 protein tended to increase with age in both WKY
and SHRs. However, the inhibitory effect of a D1-like
agonist, SKF-81297, on NHE3 activity increased with age in WKY rats (3 wk = 
40.7 ± 5.3%, n = 10, 12 wk = 58.7 ± 4.6%, n = 12, P < 0.05) but not in SHRs (3 wk = 27.6 ± 5.9%,
n = 11, 12 wk = 25.1 ± 3.2%,
n = 11). The decreased inhibitory effect of another
D1-like agonist, fenoldopam, on NHE3 activity in SHRs was
not caused by increased activity and binding of G
to NHE3 as has
been reported in young WKY rats. Gs
mediates, in part,
the inhibitory effect of D1-like agonists on NHE3 activity. In WKY rats, fenoldopam increased Gs/NHE3 binding to the
same extent in 2-wk-old (1.5-fold, n = 4) and adult
(1.5-fold, n = 4) rats. In contrast, in SHRs,
fenoldopam decreased the amount of Gs bound to NHE3 in
2-wk-old SHRs and had no effect in 4-wk-old and adult SHRs. These
studies indicate that the decreased inhibitory effect of
D1-like agonists on NHE3 activity in SHRs (compared with
WKY rats) precedes the development of hypertension. This may be caused,
in part, by a decreased interaction between Gs and NHE3
in BBM secondary to impaired D1-like receptor function.
brush-border membrane; G protein; fenoldopam; sodium/hydrogen exchanger 3
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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DOPAMINE, PRODUCED BY
RENAL proximal tubules, is an important paracrine/autocrine
inhibitor of renal sodium transport. Under conditions of moderate
sodium loading, endogenous renal dopamine accounts for >50% of sodium
excreted (28). The natriuresis is caused by inhibition of
ion and water transport in proximal and distal tubules (28, 43,
50). In the renal proximal tubule, sodium transported from
tubular fluid across the luminal membrane is mediated by cotransporters
(e.g., sodium-phosphate cotransporter) and exchangers [e.g.,
sodium/hydrogen exchanger (NHE) isoform 3; see Ref. 3].
In renal proximal tubules, dopamine inhibits NHE and sodium-phosphate
cotransporter activities at the luminal or brush-border membrane (BBM)
and Na+-HCO
In genetically hypertensive rats, however, the natriuretic effect of
exogenous and endogenous renal dopamine is attenuated markedly
(8, 16, 28, 40). This is caused by a decreased inhibitory
effect of dopamine and D1-like agonists on NHE3,
Na+-HCO
The decreased inhibitory effect of D1-like receptors on
NHE3 activity in BBM of SHR is caused, in part, by decreased
D1-like receptor generation of cAMP (1, 15, 18,
33). However, adenylyl cyclase enzyme responsiveness,
D1-like receptor density (determined by radioligand
binding), and expression of the two D1-like receptors,
D1 and D5, (determined by immunoblotting) in renal proximal tubules are not different between WKY and SHRs (1,
15, 24, 33, 53). NHE3 activity in BBM can also be inhibited to a
similar extent in WKY and SHRs if the D1-like receptor is
bypassed (24, 53). Stimulation of G proteins by guanosine
5'-O-(3-thiotriphosphate) (GTPS) inhibits NHE3 activity and increases binding of Gs to NHE3 to a similar extent
in BBMs of WKY rats and SHRs (53). However,
D1-like agonist-mediated increases of Gs and
NHE3 binding in BBMs are attenuated in SHRs compared with WKY rats.
These studies and the absence of a difference in the coding region of
D1 (and D5) receptors in SHRs support the
notion that a defective coupling of the D1-like receptors, specifically the D1 receptor, to Gs may be
responsible, in part, for the defective inhibitory action of dopamine
and D1-like agonists on NHE3 activity in renal BBMs
(1, 18, 24, 53). However, G can act to oppose
Gs action (2). In young WKY rats, the decreased D1 receptor-mediated inhibition of NHE3 activity
in BBM is caused, in part, by increased expression and binding of G dimers to NHE3 (36). It is also possible that the
defective interaction among D1-like receptors, G proteins,
second messengers, and effectors could be a consequence of the
hypertension. For example, protein kinase A (PKA) inhibits NHE3
activity in BBMs to the same extent in WKY rats and SHRs before the
establishment of hypertension (24). In adult SHRs, the
inhibitory effect of PKA on NHE3 in BBMs is attenuated compared with
the effect in WKY rats (24). Therefore, we studied these
interactions in rats before (2-4 wk) and after (12 wk) the
establishment of hypertension. To eliminate the confounding influence
of second-messenger action on D1 receptor-NHE interaction,
studies were performed in renal BBM devoid of cytoplasmic second
messengers (1, 2, 36).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Preparation of BBM vesicles.
Male WKY and SHRs 2-4 and 10-12 wk of age were used;
12-wk-old rats were considered to be adults. Two- to three-wk old rats were allowed to nurse ad libitum until the study. All rats were anesthetized with pentobarbital sodium (50 mg/kg body wt ip). Arterial
pressures were measured from the femoral artery before removal of the
kidneys. The rats were then killed by an intravenous injection of 100 mg/kg body wt of pentobarbital sodium. Renal BBM vesicles (BBMVs) were
prepared by MnCl2 precipitation and differential
centrifugation as described previously (1, 2, 12, 13, 24, 36,
53). The purity, assessed by measurement of the BBM enzymes
alkaline phosphatase and -glutamyltranspeptidase (7- to 8-fold) and
the basolateral membrane marker Na+-K+-ATPase,
is not affected by age (24). The functional NHE isoform in
renal BBMs has been shown to be caused mainly by NHE3 (2, 3, 30,
52). The studies in WKY rats and SHRs were performed concurrently with those reported for WKY rats (36).
Measurement of NHE activity. To eliminate the confounding influence of second messenger action on D1 receptor-NHE interaction, studies were performed in renal BBMVs devoid of cytoplasmic second messengers (2, 36). Therefore, phosphorylation/dephosphorylation, intermediary actions of NHE regulatory factors (NHERFs), and membrane recycling processes should not be involved in any D1-like action observed in these BBMVs (22, 54, 55).
NHE activity was determined by measuring the 100 µM 5-(N-methyl-N-isobutyl)-amiloride-sensitive uptake of 22Na+ at room temperature by the Millipore rapid filtration technique using 0.65-µm nitrocellulose filters as previously described (1, 2, 12, 13, 24, 36, 53). The BBMVs were preincubated with the D1-like agonist SKF-81297 for 30 min. Because amiloride-sensitive 22Na+ uptake at 3 s is due mainly to NHE activity, comparisons were made at this time period (13). 22Na+ uptake at 1-2 h was assumed to represent equilibrium values and also served as an index of vesicle size (13, 24).Immunoprecipitation and immunoblotting studies.
BBMVs were incubated with vehicle or a D1-like agonist
(fenoldopam, 5 × 10
6 M) for 30 min. The membranes
were lysed with ice-cold lysis buffer (PBS with 1% Nonidet P-40, 0.5%
sodium deoxycholate, 0.1% SDS, 1 mM EDTA, 1 mM EGTA, 1 mM sodium
vanadate, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, and
10 µg/ml leupeptin) for 1 h and centrifuged at 14,000 rpm for 30 min. The lysates (supernatant) were then incubated with
affinity-purified anti-NHE-3 antibody, anti-Gs,
anti-Gi-3, or anti-Gcommon antiserum for
1 h and protein A-agarose for 2-12 h at 4°C. The
immunoprecipitates were pelleted and washed with lysis buffer (4 times), boiled for 10 min, and subjected to immunoblotting. The
proteins were separated by electrophoresis (7.5% SDS-polyacrylamide
gel) and then electrophoretically transferred to nitrocellulose
membranes. The transblots were probed with the indicated antibodies,
detected by the peroxidase-conjugated secondary antibody and an
enhanced chemiluminescence system (Amersham Life, Arlington Heights,
IL), and quantified using Quantiscan (Biosoft, Ferguson, MO; see Ref.
2). For immunoblotting, 50-100 µg of protein were
loaded on a polyacrylamide gel. The amount of protein transferred to
the nitrocellulose membrane was verified by Ponceau-S stain.
Materials. Rabbit polyclonal anti-NHE3 and anti-D1 receptor antibodies were produced against a synthetic oligopeptide from the amino acid sequence of rat NHE3 (amino acids 633-646) or rat D1 receptor (amino acids 299-307; Research Genetics, Huntsville, AL; see Refs. 2 and 3). The antibodies are specific to their respective proteins as determined by Western blotting with preimmune sera or preadsorbed antibody and immunoprecipitation similar to previous reports (2).
Other materials included 5-(N-methyl-N-isobutyl)-amiloride and SKF-81297 (RBI, Natick, MA), fenoldopam (Smith Kline Beecham, King of Prussia, PA), and G protein subunit antibodies (NEN Life Science Products, Boston, MA); all other reagents were from Sigma (St. Louis, MO).Statistical analysis. Data are expressed as means ± SE. Differences within groups were analyzed by ANOVA for repeated measures (ANVR), followed by Scheffé's or Duncan's test; paired t-test was used when only two groups were compared. Differences among groups were analyzed by one-way ANOVA, followed by Scheffé's or Duncan's test; t-test was used when only two groups were compared.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Blood pressures.
Systolic blood pressure was slightly greater in SHR than in WKY rats at
3-4 wk of age (109 ± 3 vs. 97 ± 3 mmHg, respectively, n = 4/group, P < 0.05, t-test) and markedly greater in SHR (n = 22)
than in WKY rats (n = 16) at 12 wk of age (204 ± 6 vs. 122 ± 3 mmHg, respectively, P < 0.05, t-test). D1 receptors tended to decrease from 2 to 4 wk of age in both WKY rats and SHRs, reaching significance in the
latter rat strain (P < 0.05, Fig.
1A). NHE3 increased from 2 to
4 wk of age in WKY rats and tended to increase from 4 wk to adult age
in SHRs, but statistical significance was not reached
(P > 0.05 ANVR, Scheffé's test; Fig.
1B). There were no significant differences between WKY rats
and SHR at any age.
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NHE3 activity.
NHE3 activity in BBMV increased with age in WKY rats but not so in SHRs
(Fig. 2A). NHE activity was
greater in SHRs than in WKY rats at 3 wk but not at 12 wk of age. The
ability of SKF-81297, a D1-like agonist, to inhibit NHE3
activity in BBMV was less at 3 wk than at 12 wk of age, whereas
baseline NHE3 activity was greater in 12-wk than 3-wk-old WKY rats
(Fig. 2B). No difference in the effect of SKF-81297 was
noted between the 3- and 12-wk-old SHR. Regardless of age, SKF-81297
inhibited NHE3 activity to a greater extent in WKY rats than in SHRs.
The decreased ability of SKF-81297 to inhibit NHE3 activity in BBMV in
the SHR compared with WKY rats at any age could not be explained by any
strain differences in D1 receptor or NHE3 protein
expression.
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G protein subunits.
We have reported that Gs protein expression in BBM
slightly decreased with age in WKY rats (36); there was
also a trend for an age-related decrease in SHRs, but significance was
not achieved. We have also reported that another D1-like
agonist, fenoldopam (5 µM), increased the amount of Gs
bound to NHE3 to a similar extent in 2- and 12-wk-old WKY rats
(36). In the SHRs, fenoldopam had no such effect and
actually decreased the amount of Gs bound to NHE3
(compared with basal) at 2 wk of age (Fig. 3). These studies suggest that the
failure of fenoldopam in the SHR to increase the amount of
Gs bound to NHE3 with age may be the cause of absence of
the ontogenic increase in the inhibitory action of fenoldopam on NHE3
activity.
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i-3 protein expression did not change with age in WKY
rats (36) but decreased with age in SHRs (Fig.
4). In SHRs, there were no differences in
the amount of Gi-3 bound to NHE3 with age under basal
conditions (Fig. 4). In SHRs (Fig. 4), as in WKY rats (data not shown),
fenoldopam (5 µM) decreased the amount of Gi-3 bound
to NHE3 at 2 wk of age. Therefore, in SHRs, as in WKY rats
(36), Gi-3 protein does not seem to
influence basal or fenoldopam-mediated effects on NHE3 activity at any
age.
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protein expression in BBMs
decreased with age (36). In addition, fenoldopam increased the amount of G bound to NHE3 in BBMs of 2- and 4-wk-old but not in
12-wk-old WKY rats (36). In the current studies, in SHRs as in WKY rats, G expression decreased with age. However, in contrast to WKY rats, the amount of G bound to NHE3 did not change with age, either under basal conditions or after fenoldopam (5 µM)
stimulation (Fig. 5). Therefore, in SHRs,
unlike that observed in 2- and 4-wk-old WKY rats (36),
G protein does not seem to influence basal or fenoldopam-mediated
effects on NHE3 activity at any age.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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An increase in NHE3 protein abundance and activity in BBM with age has been reported in rabbits and sheep (5, 20). We also found an increase in NHE3 protein abundance and activity in BBM between 3 and 12 wk of age in WKY rats (24, 36); the current data suggest that a similar ontogenic increase in NHE3 protein abundance occurs in SHRs. NHE3 activity in proximal tubules has been reported to be greater in SHRs than in WKY rats studied before 8 wk of age; thereafter, most studies could not find a difference in basal NHE activity between these two rat strains (10, 18, 23, 24, 31, 39, 42). Because a difference was noted between WKY rats and SHR in S1 but not in S2 segments, differences among reports could have been caused by different proportions of S1 and S2 segments in any given preparation (10). In spite of these experimental limitations, a decreased ability of D1-like agonists to inhibit NHE3 activity in SHR compared with WKY rats has been found consistently (1, 18, 24). The decreased ability of D1-like agonists to inhibit NHE3 activity in SHRs compared with WKY rats could not be accounted for by differences in D1-like receptor density (24). However, two D1-like receptors, D1 and D5, are expressed in renal proximal tubules (4, 44). We now report a decreased D1-like agonist inhibition of NHE3 activity in BBM in SHRs compared with WKY rats. It was present at different ages and cannot be accounted for by differences in D1 receptor or NHE3 expression. Except for a trend for lower NHE3 protein abundance in SHRs than in WKY rats at 4 wk of age, NHE3 expressions in renal BBM were similar in WKY rats and SHRs, in agreement with some studies using proximal tubule homogenates (23, 31, 53).
We have previously noted a decreased ability of D1-like
agonists to inhibit NHE3 activity in young WKY rats (24,
36). This was not due to nonregulatable NHE3 activity because
GTPS and PKA decreased NHE3 activity to a similar extent in young
and adult WKY rats (24, 36). Because forskolin also
stimulated cAMP production in renal proximal tubules to a similar
extent in young and adult WKY rats, we suggested that the decreased
stimulatory effect on adenylyl cyclase activity and decreased
inhibitory effect on NHE3 activity in BBM by D1-like
agonists in young rats were not caused by age-related differences in
effector proteins (15, 33). Recently, the inhibitory
effect of PKA on NHE3 activity has been found to be aided by proteins
called NHERF, two of which have been identified (22). The
inhibition of phosphorylated NHE3 by ligands other than dopamine, e.g.,
parathyroid hormone, has also been shown to be associated with its
translocation from the plasma membrane to intracellular organelles
(54). Abnormalities of any of these pathways may be
responsible for the decreased inhibitory effect of D1-like
receptors on NHE3 activity in renal proximal tubules of SHRs. Indeed,
PKA inhibited NHE3 activity in renal proximal tubules to a lesser
extent in SHRs than in WKY rats (24). To avoid a
confounding effect of cytoplasmic signal transducers, we performed our
studies in BBMV devoid of cytoplasmic components.
G protein subunits can directly regulate NHE3 activity in renal BBMV
(2). Therefore, we wondered whether differences in the
coupling of D1-like receptors to G protein subunits may
also explain the decreased D1-like inhibitory effect on
NHE3 activity in the SHR. Such a differential coupling might also
explain the differences in D1-like stimulation of adenylyl
cyclase in renal proximal tubules in WKY rats and SHRs (15, 18,
33). Gs can directly inhibit NHE3 activity while
G can directly increase NHE3 activity (2). We have
suggested that increased expression and activity of G subunits
contributed to the attenuated D1-like receptor inhibition
of NHE activity in BBM of young normotensive WKY rats
(36). In SHRs, as in WKY rats, Gcommon
expression in BBM decreased with age (36). In young, but
not adult WKY rats, D1-like agonist stimulation increased
Gcommon binding in NHE3 (36). However, in
SHRs, regardless of age, D1-like agonist stimulation did
not affect the binding of Gcommon to NHE3. Thus the
attenuated effect of D1-like agonists on NHE activity in
BBM was not due to alterations in G action.
Gi-3 decreased with age in BBM in SHR but not in WKY;
however, fenoldopam did not affect the amount of Gi-3
bound to NHE3 in adult rats and decreased it in young rats in both WKY
rats and SHRs. Therefore, changes in Gi-3 expression and
binding to NHE3 do not explain the differences in D1-like
action with age in WKY rats or the differences between WKY rats and
SHRs. Furthermore, Gi-3 did not participate in the
D1-like receptor inhibition of NHE activity in BBMV
(2). Antibodies to Gi-3 also did not affect
D1-like stimulated binding of GTPS in renal proximal
tubules in either WKY rats or SHRs (26).
Gs expression tended to decrease with age in both WKY
rats and SHRs, but no differences were noted between the two strains (25, 36, 38, 47). In renal BBMs of WKY rats, there were age-related differences in the amount of Gs bound to
NHE3 after D1-like receptor stimulation (36).
In contrast, in young (current studies) and adult SHRs, the amount of
Gs bound to NHE3 was not increased by
D1-like receptor stimulation (53). GTPS
binding to renal proximal tubular basolateral membranes after
D1-like agonist stimulation was also less in SHRs than in
WKY rats at any age (26). The influence of other G
subunits was not studied. Gq expression in the kidney was
decreased in adult but not in young SHR (26, 38). Although
alterations in Gq expression may play a role in the
uncoupling of the D1-like receptor in adult hypertensive
animals, this may not be the case in young SHR (26, 28).
In the presence of calcyon, the D1 receptor becomes linked to phospholipase C- (14, 17, 29); phospholipase C-
and protein kinase C activation by D1 receptors may be
involved in the D1-like receptor inhibition of
Na+-K+-ATPase activity in the kidney
(29). Protein kinase C inhibited NHE3 activity in cells
heterologously expressing NHE3 other than the kidney (42).
However, D1-like receptor-mediated inhibition of luminal
NHE activity has been reported to be independent of phospholipase C
(14, 48). Moreover, neither D1 nor
D5, the two D1-like receptors expressed in
renal proximal tubules, is directly linked to Gq (17,
32, 37). The D1 receptor is also not linked to the
other family of G proteins, G12 and
G13 (37).
The cause of the impaired D1-like receptor function in
renal proximal tubules in genetic hypertension remains to be determined (28). Although abnormalities of G protein subunits have
been implicated in genetic hypertension, including the SHR, a primary abnormality in G proteins is unlikely in the SHR (21, 49). GTPS inhibited NHE activity in BBM to a similar extent in WKY rats
and SHRs (53). GTP and 5'-guanylyl imidodiphosphate
stimulated cAMP production in isolated proximal tubules to a similar
extent in WKY rats and SHRs (15, 33). Moreover,
reconstitution of D1 receptors from SHRs with exogenous G
proteins failed to induce formation of a high-affinity binding site
(47). We have not found differences in the sequence or
expression in renal proximal tubules of the D1 and
D5 receptors between WKY rats and SHRs (unpublished observations). We have suggested, however, that an abnormal
posttranslational modification, specifically increased serine
phosphorylation of the D1-like receptor, may be responsible
for its uncoupling from the G protein-effector complex in genetic
hypertension (45).
Modification of receptors by oxygen radicals produced in excess in
hypertension has been raised as a possible mechanism for the decreased
function of D1-like receptors in the kidney
(51). While this is possible, one would have to propose a
restricted oxygen radical formation. The uncoupling of the
D1-like receptor in rodent genetic hypertension has been
described mainly in proximal tubules and medullary thick ascending
limbs of Henle (1, 7, 8, 11, 15, 18, 24-26, 28, 33, 40,
53). The uncoupling was also not found in the striatum of the
brain where D1 receptors are expressed in greater abundance
than in renal proximal tubules (28). A general increase in
oxygen radical formation also fails to explain the organ and nephron
segment receptor-specific D1-like defect in hypertension
(28). Parathyroid hormone receptor (15, 26, 33, 34,
41), CCK-A receptor (unpublished studies), and -adrenergic
receptor functions (38) were not impaired in young SHRs
when increased reactive oxygen species is already evident (9).
We conclude that the decreased inhibitory effect of D1-like
agonists on NHE3 activity in SHRs (compared with WKY rats) precedes the
development of hypertension. In WKY rats, the enhanced NHE3 inhibition
by D1-like receptors in older rats is caused by an age-dependent decrease in G action and maintenance of the level of Gs action. In SHRs, the decreased NHE3 inhibition by
D1 receptors is not caused by G action but rather by
a decreased interaction between Gs and NHE3. Proteins
like NHERF1 and NHERF2 that regulate NHE3 activity are unlikely to be
involved in our experiments utilizing BBMV because the regulation of
NHE3 by these proteins involves cAMP (22).
Perspectives
The cause(s) of essential hypertension remains elusive, probably because it is a heterogeneous disease in which both genetics and environment contribute to elevate blood pressure. The blood pressure difference between a hypertensive strain of rat and a normotensive control has been attributed to the influence of several genetic loci. Each of the individual genetic loci that contribute incrementally to hypertension has specific biochemical or physiological phenotypes. There is considerable evidence for the involvement of dopamine and genes that regulate dopamine receptor function in the pathogenesis of hypertension. The decreased natriuretic effect of D1-like agonists in rodent genetic hypertension is not casual or strain related since this phenotype in the SHR cosegregates with high blood pressure (1). The decreased ability of dopamine and D1-like agonists to inhibit sodium transport in rodent genetic hypertension is caused by diminished D1-like inhibition of NHE3, Na+-HCO| |
ACKNOWLEDGEMENTS |
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These studies were supported by National Institutes of Health Grants DK-39308, DK-44756, HL-23081, and HL-58536.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. A. Jose, Physician's Healthcare Center, Georgetown Univ. Medical Center, 3800 Reservoir Rd. NW, Washington, DC 20007 (E-mail: pjose01{at}georgetown.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.
Received 24 February 2000; accepted in final form 20 December 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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