(Hypertension. 2001;38:255.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Cardiac ßARK1 Upregulation Induced by Chronic Salt Deprivation in Rats
From the Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Federico II University of Naples (G.I., E.B., E.C., A.E., A.F., B.T.), Naples, Italy; and the Department of Surgery, Duke University Medical Center (W.J.K.), Durham, NC.
Correspondence to Guido Iaccarino, MD, PhD, Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Federico II University, Via Pansini 5, 80131 Naples, Italy. E-mail guiaccar{at}unina.it
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Abstract— The ß-adrenergic receptor (ßAR) kinase (ßARK1) is a G protein-coupled receptor kinase (GRK) that controls cardiac ßAR signaling via receptor phosphorylation, leading to desensitization. We have observed in mice that chronic isoproterenol administration results in increased myocardial levels of ßARK1 activity, suggesting that adrenergic activation can regulate cardiac ßARK1 expression. Thus, we evaluated left ventricular (LV) ßARK1 levels and activity in response to 3 weeks of a low-sodium (0.05%) diet, which is known to chronically activate the sympathetic nervous system. Wistar-Kyoto rats were subjected to either low or regular sodium (2%) intake. To prove the association of ßARK1 expression and low sodium-induced adrenergic activation, a group of rats was subjected to atenolol treatment (1 mg/kg per day) during the low-sodium diet. LV ßARK1 expression was assessed by protein immunoblotting and ßARK1 activity by in vitro GRK phosphorylation assays. We verified the LV protein levels of GRK5, which is abundantly expressed in the heart. A low-sodium diet reduced body weight and cardiac size so that the heart-to-body weight ratio did not change. On the contrary, low-sodium diet increased by 50% both LV ßARK1 protein (densitometry units: normal sodium, 26.5±0.9; low sodium, 35.7±1.6; P<0.05) and activity (fmol/mg per minute: normal sodium, 6.49±1.17; low sodium, 9.15±0.93; P<0.05). Atenolol treatment prevented the increase in both protein expression (low sodium plus atenolol, 27.6±5.33, P=NS versus normal sodium) and activity (6.54±1.19, P=NS versus normal sodium). GRK5 expression was not affected by a low-sodium diet (17.2±0.2 versus 18.4±0.4, P=NS). Our data indicate that cardiac ßARK1 is regulated by sympathetic action on ßARs as tested by reducing dietary salt and ßAR blockade.
Key Words: G proteins • kinases • receptors, adrenergic, beta • heart • rats • signal transduction • diet
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Introduction |
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ß-Adrenergic receptors (ßARs) represent the major determinant of inotropic and chronotropic regulation of the heart. Two classes of ßAR receptor are represented in the heart, ß1 and ß2. ß1 is the most abundant type in the normal heart.
After stimulation with the agonist norepinephrine,1 both ßARs activate adenylyl cyclase via coupling to the heterotrimeric G protein Gs, stimulating the production of the second messenger, cAMP.2 Moreover, agonist occupancy of ßARs also triggers a series of events that leads to the inactivation of ßAR signaling, known as desensitization, which allows the fine regulation of ßAR signaling.3 The molecules involved in desensitization include the G protein-coupled receptor kinase (GRK) family, which in the heart is represented by GRK2, GRK3, GRK4, and GRK5 and the 2 ß-arrestins.3 A pivotal role in this mechanism is played by the GRK2, better known as the ßAR kinase 1 (ßARK1).3 This GRK can phosphorylate the active form of both ß1AR and ß2AR in the heart and uncouples the receptor from the production of the second messenger, preventing further signaling. Another GRK that is abundant in the heart is GRK5. Like ßARK1, GRK5 can phosphorylate the active form of myocardial ßAR.4
By causing ßAR desensitization, ßARK1 plays a crucial role in pathological conditions in which it is found at increased levels. In fact, several reports have shown that cardiac ßARK1 levels are increased in heart failure,5,6 myocardial ischemia,7 hypertension,8,9 and pressure overload left ventricular (LV) hypertrophy.10 The mechanisms that cause the increase in cardiac ßARK1 expression in these conditions are not completely understood. A common feature of cardiovascular diseases associated with impairment of cardiac function is the activation of neurohormonal mechanisms in an attempt to adapt the cardiac performance to the changed metabolic and hemodynamic needs. In particular, during heart failure, there is the increase of cardiac sympathetic nervous system (SNS) activity11,12 that precedes systemic sympathetic activation.13
The chronic exposure to increased levels of catecholamines is thought to be responsible for some of the alterations observed in ßAR signaling during heart failure,14 and it is possible to speculate that cardiac ßARK1 levels can also be modulated by the SNS. Alternatively, the increased levels of this GRK could be part of the changed pattern of gene expression of the failing heart.15 Indeed, we have recently demonstrated that in wild-type mice, chronic infusion of isoproterenol, a ßAR agonist, increases cardiac ßARK1 expression and activity, and ß-blockade decreases levels of ßARK1 in the heart below endogenous levels.16 Interestingly, 
-AR activation does not lead to increased ßARK1 expression in the heart.17 The exact role of the SNS in the regulation of cardiac ßARK1 is still unclear. To clarify the role of the SNS in the modulation of ßARK1 expression and activity, we used a model of chronic SNS activation, which is obtained by sodium deprivation in rats.18–20 This experimental model has the advantage of creating sympathetic activation in the absence of cardiac disease or pathological alterations. Also, to further prove the role of the SNS and ßAR during salt deprivation, we treated a group of rats with atenolol, which is a selective ß1AR antagonist and therefore interrupts the adrenergic activation of the heart.
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Materials and Methods |
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Experimental Animals, Study Design, and Miniosmotic Pump Implantation
Eight-week-old Wistar-Kyoto rats (Charles River Laboratory, Milan, Italy) were used in the study. Animals were housed 2 per cage and kept in a temperature-controlled room (between 22°C and 24°C) with a 12-hour light/dark cycle. The animals were divided in 3 groups: the first group (n=13) received a normal-sodium diet containing 2% NaCl; the second group (n=13) received a low-sodium diet containing 0.05% NaCl; and the third group (n=10) received a low-sodium diet and were exposed to chronic infusion of atenolol during the entire test diet period by means of surgically implanted miniosmotic pumps. The test diet period was 3 weeks.
Two days before the diet regimens started, rats were anesthetized with a mixture of ketamine (10 mg/kg) and xylazine (0.5 mg/kg), and a small incision was made in the skin between the scapulae. A small pocket was created by spreading apart the subcutaneous connective tissue. After insertion of the miniosmotic pump (model 2002; Alzet), the skin incision was closed with a 4.0 catgut suture. Atenolol was dissolved in 30% DMSO, and the pumps were filled to deliver atenolol at the rate of 1 mg · kg-1 · d-1. According to the manufacturer, the delivery period of this model of pumps is 28 days. As controls, pumps that delivered vehicle (30% DMSO) were implanted in rats.
At the end of treatment, rats were weighed and then decapitated. Hearts were immediately removed, rinsed 3 times in cold PBS and blotted dry, weighed, divided in LVs and right ventricles, and then rapidly frozen in liquid nitrogen and stored at -70°C until needed for biochemical studies. The LV weight-to-body weight ratio was then calculated (mg/g).
Animal procedures were performed in accordance with the guidelines of the Federico II University of Naples Institutional Animal Usage Committee.
Surgical Procedure and Blood Pressure Measurement
Three days before the end of the study, all rats were anesthetized as above, and a polyethylene catheter (PE-10) was inserted into the external carotid artery. The catheter was filled with heparinized saline (100 µU/mL) and exteriorized subcutaneous at the interscapular area. After the surgery, the animals were housed in single cages and allowed to recover. Arterial pressure was measured in conscious freely moving rats. The arterial catheter was connected to a low-volume pressure transducer connected to a computer for the analysis of the blood pressure record (Powerlab, ADI Instruments). Arterial blood pressure and heart rate were measured in each animal for 30 minutes, daily over the next 3 days. Heart rate was calculated from the arterial pressure records. For each rat, the average of the measurements performed during the 3 days was considered.
ß-Adrenoreceptor Radioligand Binding
Receptor binding on myocardial membranes was performed as previously described using the nonselective ßAR ligand [125I]-cyanopindolol.16,17 Competition binding isotherms in sarcolemmal membranes was performed as previously described21,22 in triplicate, with 12 varying concentrations of isoproterenol (from 10-12 to 10-4 M). Assays were conduced at 37°C for 60 minutes, then filtered over glass fiber membranes (Skatron), and washed and counted in a 
-counter. Competition curves were analyzed by nonlinear least-square curve fit (Graph Pad Prism).
Adenylyl Cyclase Activity
Crude myocardial membranes (20 to 30 µg of protein) were incubated for 15 minutes at 37°C with [-32P]ATP under basal conditions or in the presence of either 100 µmol/L isoproterenol or 10 mmol/L NaF, and cAMP was quantified by standard methods as we have described previously.16,17
Protein Immunoblotting
Immunodetection of myocardial levels of ßARK1 was performed on detergent-solubilized extracts after immunoprecipitation, as previously described.16,17
Rhodopsin Phosphorylation Assays
Rhodopsin phosphorylation assays on myocardial extracts were assessed as described previously.16,17
Statistical Analysis
Data are expressed as mean±SEM. ANOVA using diet as grouping factors was used to analyze the biochemical as well as the functional data. Post hoc analysis was performed according to Bonferroni correction for comparisons between groups. A P value <0.05 was considered statistically significant.23
An expanded Methods section can be found in an online data supplement available at http://www.hypertensionaha.org.
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Results |
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Heart Weight-to-Body Weight Ratios and Blood Pressure
As expected,18 the low-sodium diet reduced body weights (normal sodium, 332±5 g; low sodium, 311±8 g; P<0.05) without affecting the LV-to-body weight ratio (normal sodium, 2.14±0.09; low sodium, 2.12±0.14; P=NS). Atenolol-treated rats showed a reduction in body weight compared with that of rats on a normal-sodium diet (278±5 g P<0.05 versus normal and low sodium). Furthermore, atenolol treatment caused the reduction of the LV-to-body weight ratio (1.87±0.08; P<0.05 versus normal and low sodium). Blood pressure and heart rate were not different between normal- and low-sodium regimens, a finding that confirms previous observations.18,19 Atenolol reduced blood pressure (mean arterial pressure, mm Hg: normal sodium, 102±5; low sodium, 96±8, P=NS versus normal sodium; low sodium plus atenolol, 70±1, P<0.05 versus normal and low sodium) and heart rate (bpm: normal sodium, 381±20; low sodium, 359±31, P=NS versus normal sodium; low sodium plus atenolol, 171±9, P<0.05 versus normal and low sodium, P<0.05) as expected.
ßAR Density and Signaling
The effect of a low-sodium diet on cardiac ßAR signaling was assessed by measuring myocardial ßAR density and functional coupling to membrane adenylyl cyclase activity. A low-sodium diet resulted in a decrease in ßAR density in the heart, and atenolol attenuated this loss (Table). In addition to the decrease in ßAR density, a low-sodium diet also reduced the percentage of receptors exhibiting high affinity binding for isoproterenol (Table). Atenolol was able to prevent this phenomenon. Cardiac ßAR responsiveness to isoproterenol was impaired in the low-sodium group, and chronic atenolol treatment prevented ßAR hypo-responsiveness in the low-sodium group (Table). Responses to NaF were not statistically different among the 3 groups (Table).
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Cardiac ßARK1 Expression and Activity
To assess the possible involvement of ßARK1 in the impairment of ßAR signaling, we examined the content of ßARK1 in the 3 groups by Western blotting. As shown in Figure 1, ßARK1 was significantly elevated in the hearts of rats on low sodium; atenolol treatment prevented ßARK1 upregulation in rats on low sodium (Figure 1). Consistent with the increase in the total amount of protein, the activity of this kinase was increased after the low-sodium diet. This was found by assessing the cardiac cytosolic GRK activity as in vitro rhodopsin phosphorylation assay (Figure 2). Furthermore, atenolol prevented the increase in ßARK1 activity induced by low-sodium diet (Figure 2).
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GRK5 Expression
We also tested the possible involvement of GRK5 in the desensitization of ßAR signaling in the heart after the low-sodium diet. By Western blotting of myocardial membrane where GRK5 is located, we were unable to observe any difference in the expression of this molecule induced by low sodium (Figure 3). The effect of atenolol was not studied because we have previously shown that chronic ß-blockade does not alter myocardial GRK5 expression or activity.16
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Discussion |
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In this study, we demonstrate that sodium deprivation in rats causes alterations in cardiac ßAR affinity responsiveness assessed by adenylyl cyclase activity. Our data indicate that a primary mechanism is the reduction of the percentage of ßARs in the high affinity conformation caused by the increased expression and activity of cardiac ßARK1. Interestingly, atenolol treatment prevented the rise in ßARK1 levels in the heart and improved ßAR signaling.
The pivotal role of ßARK1 in cardiac ßAR signaling and function was first shown in transgenic mice with cardiac overexpression of this GRK.24 In that study it was shown for the first time that this regulator of ßAR signaling was able (in absence of other alterations of the excitation-contractile machinery of the heart) to dampen the cardiac contractile response to ßAR stimulation.24 After this initial study, many observational studies have associated increased cardiac ßARK1 levels to animal and human models of cardiac dysfunction.5–10 Nevertheless, very little is known about the mechanisms that lead to increased cardiac ßARK1 levels. The present study provides evidence that the SNS plays a pivotal role in the regulation of this kinase in the heart, via chronic cardiac ßAR stimulation.
Dietary sodium manipulation has been previously used to study ßAR responsiveness in cardiovascular tissues. In particular, it has been demonstrated that dietary sodium reduction improves ßAR signaling in hypertensive rat myocardium.25 Also, dietary sodium restriction reverses alterations in ßAR signaling observed in salt-sensitive experimental and human hypertension.25–27 We used a level of sodium deprivation that has been constantly demonstrated to activate the SNS in salt-resistant normotensive rats.18,19 To our knowledge, this is the first study on cardiac ßARK1 and ßAR signaling using this level of sodium restriction. Sodium deprivation decreases extracellular fluid volume and increases circulating catecholamines28 and total and renal norepinephrine spillover.29,30 These changes of SNS activity are necessary to keep arterial pressure from falling, and in fact, we did not observe any changes of arterial blood pressure induced by the low-sodium diet. It can be speculated that because the SNS is increased at the cardiac level, it would be reasonable to find increased heart rate. We and others18,19 failed to observe any difference in blood pressure and heart rate between rats on low- and normal-sodium diets. Our findings suggest that this is due to low sodium-induced desensitization of myocardial ßARs mediated via the significant upregulation of ßARK1. It is quite possible that the analysis of the hemodynamic parameters at an earlier stage would have revealed a difference in blood pressure and heart rate.
It has also been demonstrated that in this model, other neurohormonal mechanisms are activated as well, such as the renin angiotensin system.18,19 The activation of the SNS in this model appears to be dependent on the stimulation of angiotensin II receptors in the area postrema.18,19 For this reason we studied a third group of rats that were fed a low-sodium diet while receiving a ß-blocker, atenolol. This drug selectively blocks ß1ARs, which are prevalently expressed on cardiomyocyte sarcolemmal membranes. Thus, atenolol interferes with the SNS neurotransmitter norepinephrine at the cardiac level and interrupts the local adrenergic activation of the heart. In this group of animals, we observed that the alterations in cardiac ßAR and ßARK1 induced by a low-sodium diet were prevented, strongly supporting an intimate relationship between the SNS and ßARK1 through the activation of myocardial ßARs. ßARK1 downregulation and improved ßAR signaling were recently described in the heart of normotensive nonfailing mice treated chronically with atenolol or carvedilol, in absence of chronic sympathetic activation, as well as in vitro in response to propranolol,16 suggesting therefore that they are features of different types of ß-blockers, probably because of their common ability to interrupt ßAR activation in response to SNS.
We have recently reported that chronic activation of ßAR with isoproterenol results in hypertrophy with associated ßAR desensitization via an increase in ßARK1.16,17 Interestingly, ßARK1 upregulation is not a general property of myocardial hypertrophy because chronic phenylephrine treatment also caused increased cardiac mass, without changes in the level and activity of myocardial ßARK1.17 Thus, ßARK1 is regulated by stimulation of ßARs and dissociated from hypertrophy per se. In these previous studies the possibility that the increase in cardiac ßARK1 was a toxic effect of isoproterenol, or an ancillary feature of isoproterenol-induced hypertrophy, could not be excluded.
ßARK1 expression is indeed increased in cardiovascular conditions, such as cardiac dilatation,5 heart failure,6 ischemia,7 hypertension,8,9 and pressure overload cardiac hypertrophy.10 Thus, it can be speculated that ßARK1 increase is a nonspecific hallmark of disease to be included in the pattern of genetic rearrangement observed in these conditions.15 However, the present study offers a novel insight in that our results show for the first time that a physiological stimulus that produces sustained chronic SNS activation can induce an increase in cardiac ßARK1 expression and activity in otherwise normal animals. Importantly, in our study, there is not underlying cardiac dysfunction that might be responsible for the increase in cardiac ßARK1 nor is the increased ßARK1 in the heart the result of genetic manipulation. Therefore, we can conclude from our results, including the atenolol data, that increased ßARK1 levels induced by a low-sodium diet are via the activation of the SNS and, more specifically, are mediated by chronic myocardial ßAR stimulation. SNS activation has been demonstrated in many cardiovascular conditions, such as cardiac hypertrophy, cardiac ischemia, and heart failure. Therefore, it is possible to speculate that also in these conditions the SNS may play a role in cardiac ßARK1 upregulation. Further study will be needed to clarify this issue.
It appears that the cardiac regulation of ßARK1 during a low-sodium diet is selective for this kinase. Another GRK that is also abundantly expressed in the heart is GRK5.31 A recent report has shown that GRK5 is selectively upregulated in the failing heart of the paced pig.32 Using different animal models, we33,34 and others35 could not confirm this observation. In a rodent model of heart failure, however, ßAR density and signaling show changes that are consistent with the downregulation and uncoupling of receptors seen in human heart failure.36 In the present study, we evaluated GRK5 by Western blotting and could not find any changes induced by the low-sodium diet in the cardiac content of the kinase. We conclude therefore that in the normal heart, ßARK1 but not GRK5 is regulated by low sodium-induced increase in SNS. This is consistent with our previous study with chronic isoproterenol infusion in mice, which led to increases in only cardiac ßARK1 expression but not GRK5.16
In conclusion, our study suggests that the increase in the SNS causes dysfunction of the cardiac ßAR signaling via both ßAR downregulation and increased cardiac ßARK1 leading to ßAR desensitization, supporting the concept that the SNS is an important pathological element in the progression of heart failure.14 Our study did not investigate other regulators of adenylyl cyclase activation, which could also be regulated by low-sodium diet. In fact a nonsignificant tendency toward a reduced response to NaF in the sarcolemmal membranes of the LVs of rats on a low-sodium diet might suggest that other mechanisms of the ternary complex might be altered such as Gi, Gs, adenylyl cyclase isoforms. This issue has to be further evaluated in studies of cAMP production in response to other receptor activation. However, ßARK1 remains a key molecule in the control of cardiac ßAR signaling in response to chronic hemodynamic changes. We speculate that this molecule might represent an important target for the treatment of cardiovascular conditions associated with ßAR uncoupling, such as heart failure. Our result also support a hypothesis that the positive effects of ß-blockers on the outcome of human heart failure37,38 at least in part could be due to the ability of this class of drugs to reduce the cardiac content of ßARK1 and restore ßAR signaling.
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Acknowledgments |
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Guido Iaccarino is supported by a fellowship granted by Telethon, Italy. This work was funded by Telethon, Italy.
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Footnotes |
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Reprints request to Bruno Timarco, MD, Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Federico II University, Via Pansini 5, 80131 Naples, Italy. E-mail trimarco@unina.it
Received October 18, 2000; first decision November 30, 2000; accepted January 18, 2001.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- Brodde OE. ß-adrenergic receptors in failing human myocardium. Basic Res Cardiol. 1996; 91 (suppl 2): 35–40.
- Stiles GL, Lefkowitz RJ. Cardiac adrenergic receptors. Annu Rev Med. 1984; 35: 149–164.[Medline] [Order article via Infotrieve]
- Lefkowitz RJ. G protein-coupled receptor kinases. Cell. 1993; 74: 409–412.[Medline] [Order article via Infotrieve]
-
Premont RT, Koch WJ, Inglese J, Lefkowitz RJ. Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases. J Biol Chem. 1994; 269: 6832–6841.
[Abstract/Free Full Text] -
Rockman HA, Choi DJ, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ. Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. Proc Natl Acad Sci U S A. 1996; 93: 9954–9959.
[Abstract/Free Full Text] -
Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of ß-adrenergic receptor kinase and ß1-adrenergic receptors in the failing human heart. Circulation. 1993; 87: 454–463.
[Abstract/Free Full Text] -
Ungerer M, Kessebohm K, Kronsbein K, Lohse MJ, Richardt G. Activation of ß-adrenergic receptor kinase during myocardial ischemia. Circ Res. 1996; 79: 455–460.
[Abstract/Free Full Text] -
Anderson KM, Eckhart AD, Willette RN, Koch WJ. The myocardial ß-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats. Hypertension. 1999; 33: 402–407.
[Abstract/Free Full Text] - Gros R, Benovic JL, Tan CM, Feldman RD. G-protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest. 1997; 99: 2087–2093.[Medline] [Order article via Infotrieve]
-
Choi DJ, Koch WJ, Hunter JJ, Rockman HA. Mechanism of ß-adrenergic receptor desensitization in cardiac hypertrophy is increased ß-adrenergic receptor kinase. J Biol Chem. 1997; 272: 17223–17229.
[Abstract/Free Full Text] -
Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986; 73: 615–621.
[Abstract/Free Full Text] -
Meredith IT, Eisenhofer G, Lambert GW, Dewar EM, Jennings GL, Esler MD. Cardiac sympathetic nervous activity in congestive heart failure: evidence for increased neuronal norepinephrine release and preserved neuronal uptake. Circulation. 1993; 88: 136–145.
[Abstract/Free Full Text] -
Rundqvist B, Elam M, Bergmann-Sverrisdottir Y, Eisenhofer G, Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation. 1997; 95: 169–175.
[Abstract/Free Full Text] - Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with ß-blocking agents. Am J Cardiol. 1993; 71: 12C–22C.[Medline] [Order article via Infotrieve]
- Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. Faseb J. 1991; 5: 3037–3046.[Abstract]
-
Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by ß-adrenergic receptor stimulation and blockade. Circulation. 1998; 98: 1783–1789.
[Abstract/Free Full Text] -
Iaccarino G, Dolber PC, Lefkowitz RJ, Koch WJ. ß-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by ß- but not 1-adrenergic stimulation. Hypertension. 1999; 33: 396–401.
[Abstract/Free Full Text] -
Xu L, Brooks VL. Ang II chronically supports renal and lumbar sympathetic activity in sodium-deprived, conscious rats. Am J Physiol. 1996; 271(pt 2): H2591–H2598.
[Abstract/Free Full Text] - Xu L, Collister JP, Osborn JW, Brooks VL. Endogenous Ang II supports lumbar sympathetic activity in conscious sodium-deprived rats: role of area postrema. Am J Physiol. 1998; 275(pt 2): R46–R55.
- Dibona GF, Jones SY, Sawin LL. Effect of endogenous angiotensin II on renal nerve activity and its cardiac baroreflex regulation. J Am Soc Nephrol. 1998; 9: 1983–1989.[Abstract]
-
Cho MC, Rapacciuolo A, Koch WJ, Kobayashi Y, Jones LR, Rockman HA. Defective ß-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem. 1999; 274: 22251–22256.
[Abstract/Free Full Text] -
Cho MC, Rao M, Koch WJ, Thomas SA, Palmiter RD, Rockman HA. Enhanced contractility and decreased ß-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine. Circulation. 1999; 99: 2702–2707.
[Abstract/Free Full Text] - Wilkinson L. SYSTAT: The System for Statistics, 4.0 ed. Evanston, Ill: SYSTAT; 1990.
-
Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the ß-adrenergic receptor kinase or a ßARK inhibitor. Science. 1995; 268: 1350–1353.
[Abstract/Free Full Text] -
Bohm M, Gierschik P, Knorr A, Schmidt U, Weismann K, Erdmann E. Cardiac adenylyl cyclase, ß-adrenergic receptors, and G proteins in salt-sensitive hypertension. Hypertension. 1993; 22: 715–727.
[Abstract/Free Full Text] -
Limas C, Limas CJ. Cardiac ß-adrenergic receptors in salt-dependent genetic hypertension. Hypertension. 1985; 7: 760–766.
[Abstract/Free Full Text] - Feldman RD, Lawton WJ, McArdle WL. Low sodium diet corrects the defect in lymphocyte ß-adrenergic responsiveness in hypertensive subjects. J Clin Invest. 1987; 79: 290–294.
- Goldstein DS. Plasma norepinephrine as an indicator of sympathetic neural activity in clinical cardiology. Am J Cardiol. 1981; 48: 1147–1154.[Medline] [Order article via Infotrieve]
-
Friberg P, Meredith I, Jennings G, Lambert G, Fazio V, Esler M. Evidence for increased renal norepinephrine overflow during sodium restriction in humans. Hypertension. 1990; 16: 121–130.
[Abstract/Free Full Text] - Oliver JA, Pinto J, Sciacca RR, Cannon PJ. Increased renal secretion of norepinephrine and prostaglandin E2 during sodium depletion in the dog. J Clin Invest. 1980; 66: 748–756.
-
Kunapuli P, Onorato JJ, Hosey MM, Benovic JL. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. J Biol Chem. 1994; 269: 1099–1105.
[Abstract/Free Full Text] -
Ping P, Anzai T, Gao M, Hammond HK. Adenylyl cyclase and G protein receptor kinase expression during development of heart failure. Am J Physiol. 1997; 273: H707–H717.
[Abstract/Free Full Text] -
Akhter SA, Skaer CA, Kypson AP, McDonald PH, Peppel KC, Glower DD, Lefkowitz RJ, Koch WJ. Restoration of ß-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. Proc Natl Acad Sci U S A. 1997; 94: 12100–12105.
[Abstract/Free Full Text] -
Maurice JP, Shah AS, Kypson AP, Hata JA, White DC, Glower DD, Koch WJ. Molecular ß-adrenergic signaling abnormalities in failing rabbit hearts after infarction. Am J Physiol. 1999; 276(pt 2): H1853–H1860.
[Abstract/Free Full Text] - Urasawa K, Yoshida I, Takagi C, Onozuka H, Mikami T, Kawaguchi H, Kitabatake A. Enhanced expression of ß-adrenergic receptor kinase 1 in the hearts of cardiomyopathic Syrian hamsters, BIO53.58. Biochem Biophys Res Commun. 1996; 219: 26–30.[Medline] [Order article via Infotrieve]
-
Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A, Erdmann E, Lohse MJ. Expression of ß-arrestins and ß-adrenergic receptor kinases in the failing human heart. Circ Res. 1994; 74: 206–213.
[Abstract/Free Full Text] - The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999; 353: 9–13.[Medline] [Order article via Infotrieve]
-
Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group Circulation. 1996; 94: 2800–2806.
[Abstract/Free Full Text]
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 K. Leineweber, P. Rohe, A. Beilfuss, C. Wolf, H. Sporkmann, H. Bruck, H.-G. Jakob, G. Heusch, T. Philipp, and O.-E. Brodde G-protein-coupled receptor kinase activity in human heart failure: Effects of {beta}-adrenoceptor blockade Cardiovasc Res, June 1, 2005; 66(3): 512 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Iaccarino, M. Ciccarelli, D. Sorriento, E. Cipolletta, V. Cerullo, G. L. Iovino, A. Paudice, A. Elia, G. Santulli, A. Campanile, et al. AKT Participates in Endothelial Dysfunction in Hypertension Circulation, June 1, 2004; 109(21): 2587 - 2593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hata and W. J. Koch Phosphorylation of G Protein-Coupled Receptors: GPCR Kinases in Heart Disease Mol. Interv., August 1, 2003; 3(5): 264 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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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