(Hypertension. 2000;35:38.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
G-Protein–Coupled Receptor Kinase Activity in Hypertension
Increased Vascular and Lymphocyte G-Protein Receptor Kinase-2 Protein Expression
From the Departments of Medicine, Physiology and Pharmacology and Toxicology (R.G., J.C., M.D.M., R.D.F.), University of Western Ontario, London, Ontario, Canada; the John P. Robarts Research Institute (S.S.G.F., R.D.F.), London, Ontario, Canada; and the Department of Biochemistry and Molecular Pharmacology (J.L.B.), Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Dr Ross D. Feldman, Room 6L13B, LHSC-University Campus, 339 Windermere Rd, PO Box 5339, London, Ontario. Canada N6A 5A5. E-mail feldmanr{at}lhsc.on.ca
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Abstract |
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Abstract—Impaired receptor-stimulated adenylyl cyclase activation has been observed in lymphocytes from hypertensive subjects and has been linked to an increase in lymphocyte G-protein receptor kinase-2 (GRK-2) protein expression. However, whether the increase in lymphocyte GRK-2 reflected an increase in vascular GRK-2 was unknown. Therefore, we compared GRK-2 protein expression in lymphocytes and aortas obtained from normotensive Wistar rats, Wistar-Kyoto rats (WKY), and spontaneously hypertensive rats (SHR) and from aortas of Dahl rats. Impaired ß-adrenergic responsiveness was observed in lymphocytes and vascular tissues obtained from hypertensive SHR (10 and 15 weeks old) but not in those obtained from prehypertensive SHR (5 weeks old). Immunodetectable lymphocyte GRK-2 protein expression was increased in 10-week-old SHR (143±10% of the expression in 10-week-old Wistar rats and 131±11% of the expression in 10-week-old WKY, n=5 in each group). Immunodetectable vascular smooth muscle cell GRK-2 was comparably increased (169±14% of the expression in Wistar rats and 138±7% of the expression in WKY, n=5 in each group). Also, in hypertensive Dahl salt-sensitive rats, vascular GRK-2 protein expression was increased (185±14% of the expression in Dahl salt-resistant rats, n=5 in each group) compared with Dahl salt-resistant controls. These studies support a generalized defect in vascular GRK-2 protein expression in hypertension, which could be an important factor in the impairment of ß-adrenergic–mediated vasodilation, characteristic of the hypertensive state.
Key Words: G protein • adrenergic receptors • adenylyl cyclase • hypertension, essential • cyclic AMP • rats
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The basic hemodynamic abnormality in hypertension is increased peripheral resistance. This increase in peripheral resistance is due to both structural and functional factors. Functionally, peripheral resistance is the net balance between vasoconstrictor and vasodilator mechanisms. The physiological antagonism between vasoconstrictor and vasodilator mechanisms may be modified by defects in functional factors regulating these mechanisms. We and others have suggested that defects in vasodilator mechanisms shift this balance toward increased peripheral resistance (reviewed in Reference 11 ). Impaired receptor-mediated vasodilation has been reported in both human hypertension and animal models of hypertension. In rat models of hypertension, this impairment in receptor-mediated vasodilation has been reported for those receptors linked to activation of adenylyl cyclase, which include ß-adrenergic receptors, adenosine receptors, prostanoid receptors, and histamine receptors (reviewed in Reference 22 ). In human hypertension, impaired ß-adrenergic–mediated vasodilation has also been observed, primarily in younger white borderline hypertensive subjects.3 4
To explain this defect in receptor-mediated vasodilation in hypertension, we and others have focused on the receptor/G-protein/adenylyl cyclase transmembrane signaling system. Impaired vascular and renal adenylyl cyclase responsiveness to hormones acting through receptors linked to the stimulatory G protein (Gs) has been reported in rat models of hypertension (reviewed in Reference 22 ).
In human hypertension, we have focused on the lymphocyte ß-adrenoceptor/Gs/adenylyl cyclase complex as a model for the vascular ß-adrenoceptor/Gs/adenylyl cyclase complex. We and others have shown that regulation of the lymphocyte ß-adrenoceptor complex parallels the regulation of functional vascular ß-adrenergic responsiveness.4 5 In a series of studies, we demonstrated that (1) lymphocyte ß-adrenergic responsiveness was impaired in the hypertensive state, (2) this reflected an impairment in receptor/G-protein coupling,6 7 8 and (3) the molecular basis of this defect in receptor/G-protein coupling may relate to an increase in expression of a G-protein–coupled receptor kinase (GRK).9 10 GRKs are a family of enzymes that specifically phosphorylate agonist-occupied G-protein–linked receptors.11 12 13
The present studies were performed to determine whether, in hypertension, the increase in lymphocyte GRK-2 expression was reflected by a parallel alteration in vascular GRK-2 expression. Data to be presented demonstrate that in both spontaneously hypertensive and Dahl models of hypertension, vascular GRK-2 protein expression is upregulated, providing a potential mechanism for the impairment in vascular responsiveness characteristic of the hypertensive state.
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Methods |
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Animal Protocol
Male spontaneously hypertensive rats (SHR), normotensive Wistar rats, normotensive Wistar Kyoto rats (WKY), and Rapp Dahl salt-sensitive and salt-resistant rats (100 to 350 g, Harlan Sprague Dawley, Inc, Indianapolis, Ind) were used. The rats were cared for in accordance with the Canadian Council on Animal Care guidelines and housed under a 12-hour light/dark cycle with free access to standard laboratory rat chow and drinking water. For both Dahl salt-sensitive and salt-resistant rats, laboratory chow was supplemented with 8% NaCl. Indirect tail-cuff measurements of systolic blood pressure (SBP) were obtained in lightly anesthetized rats (1% to 1.5% halothane in a mixture of 50% nitrous oxide and 50% oxygen) by use of a Harvard rat tail monitor. Mean SBP in 5-week-old WKY was 102±5 mm Hg. In 5-week-old SHR, mean SBP was 98±4 mm Hg. In all 10-week-old SHR studied, SBP was >125 (mean SBP 138±2 mm Hg). In all 10-week-old Wistar rats and WKY studied, SBP was <110 (mean SBP 96±4 mm Hg [Wistar] and 94±2 mm Hg [WKY]). In 15-week-old SHR, mean SBP was 154±5 mm Hg (with no pressure <135 mm Hg). In all 15-week-old WKY, SBP was <115 (mean SBP 108±3 mm Hg). In Dahl salt-sensitive rats after 4 weeks of NaCl-supplemented diet, mean SBP was 156±7 mm Hg (with no pressure <140 mm Hg). In Dahl salt-resistant rats, mean SBP was 122±2 mm Hg (with no pressure >130 mm Hg). All terminal procedures were performed after anesthesia with 5% halothane.
Lymphocyte Preparation
Whole blood was obtained from rats by cardiac puncture, and
mononuclear leukocytes were separated from heparin-anticoagulated whole
blood by the method of Böyum.14 For assessment of
adenylyl cyclase activity in rat lymphocytes, permeable cells were
prepared as previously described.9 For assessment of GRK-2
protein expression, whole-cell lymphocyte samples were obtained as
described above, pelleted, and frozen at -80°C.
Preparation of Isolated Aortic Vascular Smooth Muscle Cells
and Proteins
Freshly isolated thoracic aortas (prepared with use of our
previously published techniques15 ) were placed into a
Petri dish containing ice-cold physiological salt
solution (mmol/L: NaCl 130, HEPES 20, D-glucose 10, KCl 5,
CaCl2 1, and MgCl2 1, pH
7.4) and extensively cleaned of adventitial fat and connective tissue
by use of fine forceps and scissors. The thoracic aortas were cut into
longitudinal strips 
20 to 30 mm long and 5 mm wide. The
aortic strips were then transferred to 2 mL of dissociation solution
(physiological salt solution plus 0.25 mmol/L
EDTA, 1.2 mg/mL BSA, 1 mg/mL papain, 0.8 mg/mL Sigma blend
collagenase, and 0.09 mg/mL dithiothreitol, pH 7.0) and
incubated at 37°C for 1 hour. Tissue was teased apart by triturating
with a Pasteur pipette. Undigested material was removed with forceps.
The vascular preparation was centrifuged at 500g for
10 minutes at 4°C. The pellet was resuspended in
physiological salt solution and transferred to
microfuge tubes and frozen at -80°C until needed. As an alternative
to isolated vascular smooth muscle cells, we prepared thoracic aortic
lysates as follows: clean thoracic aortic strips were placed in
microfuge tubes with 400 µL lysis buffer (100 mmol/L NaCl, 1%
Triton X-100, 10% glycerol, 50 mmol/L HEPES [pH 7.4], and
1 mmol/L EDTA) and incubated at 4°C for 1 hour. After
incubation, microfuge tubes and tissues were frozen at -80°C until
needed.
Assessment of GRK Protein Expression
Assessment of GRK protein expression was determined by
immunoblotting (as previously described in References 9
and 109 10 ). GRK-2 protein expression was determined by using a 1:100
dilution (for lymphocyte studies) or a 1:10 dilution (for vascular
smooth muscle studies) of a mouse monoclonal antibody 3A10 raised
against purified recombinant bovine GRK-2 (as previously described in
Reference 99 ). Immunoreactivity was detected with the enhanced
chemiluminescence detection system (ECL, Amersham Corp). Submaximally
exposed autoradiographs were assessed densitometrically by using NIH
Image 1.6 software. Initial studies determined that under these
conditions the assay was linear in the range of protein concentrations
used.
Assays of Adenylyl Cyclase Activity in Permeabilized
Lymphocytes
Adenylyl cyclase activity was determined in
permeabilized lymphocytes according to our previously
published methods.8 ß-Adrenoceptor stimulation of
adenylyl cyclase activity was assessed in the presence of isoproterenol
(100 µmol/L) and GTP (100 µmol/L). Maximal catalytic
activity was assessed with forskolin (10 µmol/L). Isoproterenol
and forskolin-stimulated activities were expressed relative to
GTP-stimulated activity. This proportional method of expression was
selected prospectively and is consistent with that used in our
previous studies comparing stimulated levels of adenylyl cyclase
activity in subject groups.8 9 10
Assessment of Tension in the Aortic Ring Segments
Assessment of tension in the aortic ring segments was performed
according to our previously described methods.15 After the
equilibration, rings were maximally preconstricted with
phenylephrine (3 µmol/L) and allowed to reach a
plateau. Relaxation was assessed in response to a single addition of
isoproterenol (10 µmol/L) or sodium nitroprusside (10 nmol/L).
Relaxation response with isoproterenol and nitroprusside was quantified
by determination of the area above the relaxation response curve by use
of a trapezoidal method of analysis as previously
described.15
Analysis
Those parameters expressed as a ratio (eg,
isoproterenol-stimulated adenylyl cyclase activity expressed relative
to GTP-stimulated activity) are log-normally
distributed.16 Therefore, these data were log-transformed
for statistical analysis (t test, correlations). A
value of P<0.05 on a 2-tailed 2-group test was used as a
minimum level of significance.
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Results |
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Alterations in SHR Lymphocyte ß-Adrenergic–Stimulated Adenylyl Cyclase Activity
Isoproterenol-stimulated adenylyl cyclase activity was significantly reduced in lymphocytes from 10-week-old SHR compared with 10-week-old Wistar rats, to an extent comparable to that previously seen in borderline/mildly hypertensive human subjects (Figure 1A). In contrast, GTP-stimulated adenylyl cyclase activity was not significantly altered (2.98±0.87 pmol/min per 106 cells [SHR] and 2.57±0.59 pmol/min per 106 cells [Wistar]). Additionally, forskolin-stimulated activity was not significantly altered in lymphocytes from SHR (Figure 1B).
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Alterations in Lymphocyte GRK-2 Protein Expression in SHR
Paralleling the decrease in isoproterenol-stimulated adenylyl
cyclase activity in lymphocytes from 10-week-old SHR, there was a
significant increase in GRK-2 protein expression compared with either
10-week-old Wistar rats (143±10% of expression in Wistar rats,
P<0.05, n=5 in each group; Figure 2) or WKY (131±11% of expression in
WKY, P<0.05, n=5 in each group).
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Alterations in Isoproterenol-Mediated Relaxation in SHR Aortic
Ring Segments
In aortic ring segments isolated from 10-week-old SHR, Wistar
rats, and WKY, there was an age-dependent and blood pressure–dependent
impairment in vascular ß-adrenergic–mediated response in SHR.
Maximal phenylephrine-mediated constriction was not
significantly different between WKY or Wistar rats and SHR (data not
shown). In phenylephrine-precontracted aortic ring
segments, the addition of isoproterenol resulted in a rapid relaxation
(reaching a nadir by 5 minutes). The extent of maximal relaxation was
significantly attenuated in SHR compared with Wistar rats and WKY
(Table). In contrast, responses to doses of
nitroprusside that mediated an extent of relaxation comparable to that
seen with isoproterenol were not altered between SHR and Wistar rats
(Table).
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Alterations in Vascular GRK-2 Protein Expression
GRK-2 protein expression was increased in vascular smooth muscle
cells of 10-week-old SHR versus either 10-week-old Wistar rats or WKY,
with both expressed on an absolute basis (Figures 3 and 4)
and as a proportion of 
-actin expression (GRK-2/-actin ratio
1.00±0.18 normalized arbitrary units [Wistar] and 1.79±0.17
normalized arbitrary units [SHR], P=0.015). Relative
-actin expression was not significantly altered in SHR (data not
shown).
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We also obtained aortas from Dahl salt-sensitive and -resistant
rats after 4 weeks of a high salt diet. Vascular GRK-2 protein
expression was significantly increased (185±14% of expression in Dahl
salt-resistant rats, P<0.05) in aortic tissue
lysates obtained from Dahl salt-sensitive rats compared with Dahl
salt-resistant rats. Relative -actin expression was not
different (data not shown).
Developmental Regulation of Vascular Reactivity and GRK-2
Expression
To examine the developmental relation among vascular
ß-adrenergic responsiveness, GRK-2 expression, and blood pressure, we
examined SHR and WKY at 5 weeks (prehypertensive), 10 weeks, and 15
weeks of age. In all age groups (5-, 10-, and 15-week-old rats),
maximal phenylephrine-mediated constriction was not
significantly different between SHR and WKY (data not shown). In
contrast to the impairment in ß-adrenergic–mediated relaxation in
adult (10-week-old) SHR, no alterations in isoproterenol-mediated
relaxation were observed in 5-week-old rats (Table). Notably,
compared with 5-week-old and 10-week-old WKY, 15-week-old SHR and WKY
exhibited a parallel impairment in both sodium nitroprusside–mediated
and isoproterenol-mediated relaxation (P<0.02,
Table). The impairment in both sodium nitroprusside–mediated
and isoproterenol-mediated relaxation is consistent with a
defect "downstream" from the receptor/G-protein/enzyme complex.
However, even when normalized for the impairment in sodium
nitroprusside–mediated vasodilation, an impairment in
isoproterenol-mediated relaxation was still evident in 15-week-old SHR
compared with WKY (Table).
To examine the developmental regulation of vascular GRK-2 protein
expression, we examined aortic tissue lysates obtained from 5-, 10-,
and 15-week-old SHR versus WKY. GRK-2 protein expression was comparably
increased in hypertensive rats at both 10 and 15 weeks of age in SHR
versus WKY (138±7% of the expression in 10-week-old WKY and 147±11%
of expression in 15-week-old WKY, Figure 4). Notably, GRK-2
protein expression was reduced in 5-week-old (prehypertensive) SHR
compared with 5-week-old WKY (81±10% of the GRK-2 expression observed
in 5-week-old WKY, Figure 4). Overall, in WKY, vascular GRK-2
protein expression decreased with increasing age, whereas vascular
GRK-2 protein levels in SHR did not demonstrate significant alteration
with increasing age (Figure 4). Relative -actin protein
expression was not significantly altered between SHR and WKY and did
not change from 5 to 15 weeks of age (data not shown).
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Discussion |
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We recently demonstrated that in hypertensive subjects an increase in lymphocyte GRK activity and GRK-2 expression parallels the reduction in lymphocyte ß-adrenergic–mediated adenylyl cyclase activity.9 10 The present study demonstrates that lymphocyte ß-adrenergic–stimulated adenylyl cyclase activity in SHR is reduced (comparable to that previously seen in lymphocytes from human hypertensive subjects) and that this parallels an increase in lymphocyte GRK-2 expression. Furthermore, the increase in GRK-2 protein expression is also evident in vascular smooth muscle cells from SHR with developed hypertension and Dahl salt-sensitive hypertensive rats, and this is associated with an impairment in ß-adrenergic–mediated vascular relaxation (again comparable to that previously seen in human hypertension). Moreover, we demonstrate an age-dependent decrease in vascular GRK-2 protein expression in normotensive WKY. This decrease in vascular GRK-2 does not appear to occur in SHR.
We have previously speculated that the increase in lymphocyte GRK-2 expression in human hypertensive subjects was likely not restricted to lymphocytes (ie, might be generalized to vascular smooth muscle cells), and if so, it might account for the reduction in vascular ß-adrenergic responsiveness demonstrated in both human hypertension9 and in rat models of hypertension.2 The present studies support this hypothesis. SHR have been used commonly for the study of ß-adrenergic receptor systems in hypertension (reviewed in Reference 22 ). Impaired isoproterenol-mediated vasodilation and impaired isoproterenol-stimulated adenylyl cyclase activation in vascular tissues have been previously demonstrated in this model. In the present study, we demonstrate that ß-adrenergic–mediated adenylyl cyclase activity in lymphocytes from SHR is impaired to an extent comparable to that previously reported in studies of vascular smooth muscle cells (reviewed in Reference 22 ) and similar to the extent of impairment seen in lymphocytes from human hypertensive subjects.9 13 Thus, this observation reiterates the utility of the lymphocyte as a model for the vascular ß-adrenoceptor complex in hypertension.
The reduction in ß-adrenergic–mediated adenylyl cyclase activity was associated with an increase in GRK-2 protein expression in both lymphocytes and vascular smooth muscle cells. This relative increase in GRK-2 protein expression in hypertensive rats is comparable to the increase in GRK-2 protein expression in lymphocytes from hypertensive subjects. In total, these studies suggest a more generalized defect in GRK-2 expression both in animal models of hypertension and human hypertensive subjects as well as in lymphocytes and myocytes.
The linkage between increased GRK-2 protein expression and increased blood pressure has yet to be determined. In this regard, we examined age-dependent changes in both blood pressure and GRK-2 protein expression in SHR and WKY. The relative increase in GRK-2 protein expression in SHR was apparent only in conjunction with established hypertension and was not apparent in the prehypertensive stage (up to 5 weeks of age). Notably, we observed an age-dependent decrease in vascular GRK-2 expression in normotensive WKY. In contrast, vascular GRK-2 protein expression did not decrease with increasing age in SHR. The reason for the observed developmental decrease in vascular GRK-2 protein expression with age, apparent in normotensive rats, is unknown. However, in this context, the relative increase in GRK-2 protein expression in SHR might be seen as a failure in the developmental downregulation that occurs in normotensive animals.
The mechanisms regulating GRK-2 protein expression are unclear. Our previous studies have suggested that the increase in GRK-2 protein expression was not due to an increase in GRK-2 mRNA expression.13 Developmental regulation of GRK-2 has been reported neonatal rats.17 In addition, recent data have shown that GRK-2 protein expression is regulated via a proteasomal degradation pathway.18 Whether this pathway is altered in hypertension (or with age) is unknown. However, if this pathway is important in developmental regulation of GRK-2 expression and is defective or absent in SHR, the net result might be a relative increase in GRK-2 protein expression in aging SHR compared with aging WKY. This hypothesis is the focus of ongoing studies.
In conclusion, our studies in SHR demonstrate that the increase in GRK-2 expression is evident in both lymphocytes and vascular smooth muscle cells and parallels an impairment of ß-adrenergic–mediated adenylyl cyclase activity (comparable to that seen in human hypertension) and ß-adrenergic–mediated vasodilation. In addition, increased vascular GRK-2 protein expression was also observed in hypertensive Dahl rats, suggesting a conserved change in GRK-2 protein expression across different rat models of hypertension. Overall, our findings support the hypothesis that an alteration in GRK function could underlie the defect in G-protein–coupled receptor-mediated adenylyl cyclase activation contributing to the impairment in vascular function characteristic of the hypertensive state.
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Acknowledgments |
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These studies were supported by grants-in-aid from the Medical Research Council of Canada (MT-10871 to Dr Feldman) and from the National Institutes of Health (GM-44944 to Dr Benovic). Dr Feldman is supported by a Career Investigator Award from the Heart and Stroke Foundation of Ontario. Dr Benovic is an Established Investigator of the American Heart Association. Dr Ferguson is supported by a MacDonald Scholarship Award from the Heart and Stroke Foundation of Ontario.
Received April 9, 1999; first decision May 10, 1999; accepted August 12, 1999.
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References |
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1. Brodde O-E, Martin MC. Adrenergic receptors and their signal transduction mechanisms in hypertension. J Hypertens. 1992;10(suppl 7):S133–S145.
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 A. A. Banday, F. R. Fazili, and M. F. Lokhandwala Oxidative Stress Causes Renal Dopamine D1 Receptor Dysfunction and Hypertension via Mechanisms That Involve Nuclear Factor-{kappa}B and Protein Kinase C J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1446 - 1457. [Abstract] [Full Text] [PDF]
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 R. Gros, Q. Ding, J. Chorazyczewski, J. Andrews, J. G. Pickering, R. A. Hegele, and R. D. Feldman The Impact of Blunted beta-Adrenergic Responsiveness on Growth Regulatory Pathways in Hypertension Mol. Pharmacol., January 1, 2006; 69(1): 317 - 327. [Abstract] [Full Text] [PDF]
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 J. R. Keys, R.-H. Zhou, D. M. Harris, C. A. Druckman, and A. D. Eckhart Vascular Smooth Muscle Overexpression of G Protein-Coupled Receptor Kinase 5 Elevates Blood Pressure, Which Segregates With Sex and Is Dependent on Gi-Mediated Signaling Circulation, August 23, 2005; 112(8): 1145 - 1153. [Abstract] [Full Text] [PDF]
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 A. Vroon, A. Kavelaars, V. Limmroth, M. S. Lombardi, M. U. Goebel, A.-M. Van Dam, M. G. Caron, M. Schedlowski, and C. J. Heijnen G Protein-Coupled Receptor Kinase 2 in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis J. Immunol., April 1, 2005; 174(7): 4400 - 4406. [Abstract] [Full Text] [PDF]
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 C. Zeng, H. Sanada, H. Watanabe, G. M. Eisner, R. A. Felder, and P. A. Jose Functional genomics of the dopaminergic system in hypertension Physiol Genomics, November 17, 2004; 19(3): 233 - 246. [Abstract] [Full Text] [PDF]
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 A. Dinudom, A. B. Fotia, R. J. Lefkowitz, J. A. Young, S. Kumar, and D. I. Cook The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels PNAS, August 10, 2004; 101(32): 11886 - 11890. [Abstract] [Full Text] [PDF]
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 V. Simon, M.-T. Robin, C. Legrand, and J. Cohen-Tannoudji Endogenous G Protein-Coupled Receptor Kinase 6 Triggers Homologous {beta}-Adrenergic Receptor Desensitization in Primary Uterine Smooth Muscle Cells Endocrinology, July 1, 2003; 144(7): 3058 - 3066. [Abstract] [Full Text] [PDF]
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D. Leosco, G. Iaccarino, E. Cipolletta, D. De Santis, E. Pisani, V. Trimarco, N. Ferrara, P. Abete, D. Sorriento, F. Rengo, et al. Exercise restores {beta}-adrenergic vasorelaxation in aged rat carotid arteries Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H369 - H374. [Abstract] [Full Text] [PDF]
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R. S. Ostrom, X. Liu, B. P. Head, C. Gregorian, T. M. Seasholtz, and P. A. Insel Localization of Adenylyl Cyclase Isoforms and G Protein-Coupled Receptors in Vascular Smooth Muscle Cells: Expression in Caveolin-Rich and Noncaveolin Domains Mol. Pharmacol., November 1, 2002; 62(5): 983 - 992. [Abstract] [Full Text] [PDF]
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M. S. Lombardi, A. Kavelaars, P. Penela, E. J. Scholtens, M. Roccio, R. E. Schmidt, M. Schedlowski, F. Mayor Jr., and C. J. Heijnen Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism Mol. Pharmacol., August 1, 2002; 62(2): 379 - 388. [Abstract] [Full Text] [PDF]
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R. D. Feldman Deactivation of Vasodilator Responses by GRK2 Overexpression: A Mechanism or the Mechanism for Hypertension? Mol. Pharmacol., April 1, 2002; 61(4): 707 - 709. [Full Text] [PDF]
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A. D. Eckhart, T. Ozaki, H. Tevaearai, H. A. Rockman, and W. J. Koch Vascular-Targeted Overexpression of G Protein-Coupled Receptor Kinase-2 in Transgenic Mice Attenuates beta -Adrenergic Receptor Signaling and Increases Resting Blood Pressure Mol. Pharmacol., April 1, 2002; 61(4): 749 - 758. [Abstract] [Full Text] [PDF]
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R. A. Felder, H. Sanada, J. Xu, P.-Y. Yu, Z. Wang, H. Watanabe, L. D. Asico, W. Wang, S. Zheng, I. Yamaguchi, et al. G protein-coupled receptor kinase 4 gene variants in human essential hypertension PNAS, March 19, 2002; 99(6): 3872 - 3877. [Abstract] [Full Text] [PDF]
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R. M. Carey Renal Dopamine System: Paracrine Regulator of Sodium Homeostasis and Blood Pressure Hypertension, September 1, 2001; 38(3): 297 - 302. [Abstract] [Full Text] [PDF]
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 W. E. Schutzer, J. F. Reed, M. Bliziotes, and S. L. Mader Upregulation of G protein-linked receptor kinases with advancing age in rat aorta Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R897 - R903. [Abstract] [Full Text] [PDF]
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M. S. Lombardi, A. Kavelaars, P. M. Cobelens, R. E. Schmidt, M. Schedlowski, and C. J. Heijnen Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System J. Immunol., February 1, 2001; 166(3): 1635 - 1640. [Abstract] [Full Text] [PDF]
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J. Marcil and M. B. Anand-Srivastava Lymphocytes from spontaneously hypertensive rats exhibit enhanced adenylyl cyclase-Gi protein signaling Cardiovasc Res, January 1, 2001; 49(1): 234 - 243. [Abstract] [Full Text] [PDF]
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W. E. Schutzer, H. Xue, J. F. Reed, J.-B. Roullet, S. Anderson, and S. L. Mader Angiotensin II enhances beta -adrenergic receptor-mediated vasorelaxation in aortas from young but not old rats Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2807 - H2814. [Abstract] [Full Text] [PDF]
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P. Yu, L. D. Asico, G. M. Eisner, U. Hopfer, R. A. Felder, and P. A. Jose Renal Protein Phosphatase 2A Activity and Spontaneous Hypertension in Rats Hypertension, December 1, 2000; 36(6): 1053 - 1058. [Abstract] [Full Text] [PDF]
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J. Xu, X. X. Li, F. E. Albrecht, U. Hopfer, R. M. Carey, and P. A. Jose Dopamine1 Receptor, Gs{alpha}, and Na+-H+ Exchanger Interactions in the Kidney in Hypertension Hypertension, September 1, 2000; 36(3): 395 - 399. [Abstract] [Full Text] [PDF]
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