(Hypertension. 1999;33:402-407.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
The Myocardial ß-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats
Presented in part at the 52nd Annual Fall Conference and Scientific Sessions of the American Heart Association, sponsored by American Heart Association's Council for High Blood Pressure Research, Philadelphia, Pa, September 15–18, 1998.
From the Department of Cardiovascular Pharmacology (K.M.A., R.N.W.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa; and the Department of Surgery (A.D.E., W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Dr Karen M. Anderson, SmithKline Beecham Pharmaceuticals, PO Box 1539, 709 Swedeland Rd, UW2510, King of Prussia, PA 19406. E-mail Karen_M_Anderson{at}SBPHRD.com
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Abstract |
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Abstract—Responsiveness to ß-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced ß-adrenergic receptor (ßAR) density, elevated ß-adrenergic receptor kinase 1 (ßARK1) levels, and functional uncoupling of remaining receptors. The temporal nature of changes in the human myocardial ß-adrenergic system relative to onset of symptomatic heart failure (HF) has been difficult to discern. A relatively new model of HF, the spontaneously hypertensive heart failure (SHHF) rat spontaneously and reproducibly develops left ventricular hypertrophy (LVH) and progresses to HF, thus enabling longitudinal studies to examine the cellular and molecular bases for hypertension-induced cardiac hypertrophy and subsequent HF. The purpose of this study was to examine age-dependent changes in the ßAR system in this model. Lean male SHHF rats at 3, 7, 14, and 20 months were compared with age-matched Sprague-Dawley (SD) control rats ([C]; 4 animals/group). At all ages the SHHF rats had elevated blood pressures and left ventricular end-diastolic pressure relative to the SD control rats (P<0.05). Compared with age-matched SD control rats, LVH was evident by 3 months in SHHF rats; 20-month-old SHHF rats had significantly greater LVH compared with the other SHHF rat groups. ß-adrenergic responsiveness (maximal heart rate to isoproterenol) was reduced only in 20-month-old SHHF rats. ßARK1 protein levels and activity were elevated at 14 months (162±10% and 195±20% C, respectively), and ßARK1 protein remained elevated at 20 months (140±14% C). In contrast, G protein–coupled receptor kinase 5, a second receptor kinase in the heart, remained unchanged at all ages. ßAR density did not change with age in the SD control rats and was similar in the SHHF rats until 20 months of age when the receptor number was reduced (30±1%). These data indicate that cardiac dysfunction is coincident with reduced ßAR density. Importantly, cardiac dysfunction was preceded by elevated ßARK1 levels and activity, thus suggesting that ßARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF. Furthermore, these results indicate that the SHHF rat is a powerful model for use in examination of the mechanisms involved in alterations of ß-adrenergic signaling that occur in human HF.
Key Words: hypertension, experimental • hypertrophy, cardiac • heart failure • receptors, adrenergic, beta • kinase • adenylyl cyclase • rats, inbred SHR
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypertension and hypertension-induced cardiac hypertrophy are recognized risk factors for the development of heart failure (HF). The fundamental molecular mechanisms involved in the initial compensatory hypertrophic response to elevated systemic pressures and subsequent progression to HF remain largely undefined. It has been proposed that desensitization of the ß-adrenergic signaling system contributes to the progression from hypertrophy to HF.1 Indeed, patients with chronic HF demonstrate reduced cardiac ß-adrenergic receptor (ßAR)–mediated responsiveness in the face of high circulating catecholamine levels.2 3 4 5 6 Evaluation of ventricular samples from patients with near-end or end-stage HF indicates that in HF there is reduced ßAR density,6 7 8 9 elevated levels and activity of ß-adrenergic receptor kinase 1 (ßARK1), which functionally uncouples ßARs,10 11 12 13 alterations in G proteins,7 14 15 16 17 and decreased adenylyl cyclase (AC) activity.18 19 20 Difficulty in obtaining serial ventricular samples from patients with HF and variability in changes in ß-adrenergic signaling in different contrived models of heart failure7 render it difficult to distinguish whether such changes are causally related or merely correlative with progression to symptomatic HF.
A relatively new genetic model of hypertension-induced heart failure, the spontaneously hypertensive heart failure (SHHF/Mcc-facp) rat, is now commercially available. Originally derived from a cross between spontaneously hypertensive rats (SHR) and Koletsky obese rats, and then bred to SHR at the NIH (SHR-N), the colony had been maintained by McCune (Mcc designation) at the Ohio State University.21 These rats exhibit early-onset hypertension, and all animals develop HF. While in HF the SHHF rats exhibit numerous symptoms and biochemical changes that parallel documented changes in patients with hypertension, cardiomyopathy, and HF.21 22 23 24 25 26 27 Evaluation of SHHF animals at different ages should facilitate elucidation of mechanisms temporally and causally involved in the progression from stable compensatory myocardial hypertrophy to HF. Thus, the purpose of this study was to functionally and biochemically evaluate components of the ßAR signaling cascade over a wide range of ages in lean males from this unique genetic model of HF.
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Methods |
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Assessment of Hemodynamics and Heart Weight in the SHHF and Sprague-Dawley Rats
Lean male SHHF (n=16; Genetic Models, Inc, Indianapolis, IN) rats and Sprague-Dawley (SD; n=16; Charles River Laboratories, Raleigh, NC) rats were housed in an accredited laboratory animal facility, and all procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (US Department of Health, Education, and Welfare, Department of Health and Human Services, NIH Publication 85-23). All procedures were approved by the Animal Care and Use Committee at SmithKline Beecham Pharmaceuticals.
In all animals, anesthesia was induced with isoflurane (4% in O2), and a catheter was placed in the femoral vein for the administration of drugs. Isoflurane was discontinued, and anesthesia was maintained with pentobarbital (35 mg/kg, IV; with 5 mg/kg supplemental doses as needed). The right common carotid artery was exposed, and a micro-tipped pressure transducer (Millar Instruments) was inserted retrogradely for recording arterial blood pressure. The transducer was then advanced into the left ventricle to record left ventricular pressures. Left ventricular end-diastolic pressure (LVEDP) and the maximum rates of contraction (+dP/dT) and relaxation (–dP/dT) were derived from the left ventricular pressure pulse. After these ventricular recordings had been made, the pressure transducer was again withdrawn into the common carotid artery for the determination of the maximum chronotropic response and the maximum vasodepressor response elicited by isoproterenol (10 µg/kg, IV). The heart rate tachometer was triggered by the arterial pressure pulse. Each hemodynamic evaluation was completed within 30 to 40 minutes. At the termination of the functional study, the animal was euthanized, and the heart was removed. Weights were obtained for the combined left ventricle/septum (LV+S). The samples were snap-frozen in liquid nitrogen and stored at -80°C.
Determination of ßAR Density
Total ßAR density was determined using myocardial sarcolemmal
membranes.28 Portions of the LV+S of SD or SHHF rats were
homogenized in ice-cold buffer A (25 mmol/L Tris–HCl
[pH 7.5], 5 mmol/L EDTA, 5 mmol/L EGTA, 10 mg/mL leupeptin,
20 mg/mL aprotinin, and 1 mmol/L phenylmethylsulfonyl
fluoride). Nuclei and tissue were separated by
centrifugation at 800g for 15 minutes. The
crude supernatant was then centrifuged at 20 000g
for 15 minutes. Protein concentrations were determined using Bradford
reagent (Pierce) on the supernatant (cytosolic fraction). Sedimented
proteins (membrane fraction) were resuspended in 50 mmol/L HEPES
(pH 7.3) and 5 mmol/L MgCl2. ßAR binding
was determined by incubating 25 µg of sarcolemmal membranes with a
saturating concentration of [125I]cyanopindolol
and 20 mmol/L alprenolol to define nonspecific
binding.28
Western Blot Analysis of ßARK1 Protein Levels
Immunoblotting of ßARK1 was performed on 500
µg of protein from the left ventricular cytosolic
fraction after immunoprecipitation with a monoclonal ßARK1/ßARK2
antibody as described previously.28 29 The ßARK1 protein
was visualized with a monoclonal antibody raised against an epitope
within the carboxyl terminus of ßARK1 and chemiluminescent detection
of anti-mouse IgG conjugated with horseradish peroxidase (Renaissance;
Amersham). To detect G protein–coupled receptor kinase 5 (GRK5), 30
µg of protein from the LV+S membrane fraction was loaded on a 12%
Tris-glycine gel. GRK5 was visualized with a monoclonal antibody to the
carboxy-terminus and chemiluminescent detection of anti-mouse
IgG.30
Evaluation of ßARK1 Activity
ßARK1 activity was determined in LV+S cytosolic fractions with
rhodopsin-enriched rod outer segment membranes as an in vitro substrate
and [
-32P]ATP as described
previously.28 [32P] incorporation
into rhodopsin was quantified by using a Molecular Dynamics
PhosphorImager.28
Determination of AC Activity
AC activity was determined on 20 µg of left
ventricular sarcolemmal membranes in
triplicate.28 Membranes were incubated for 15 minutes at
37°C with [
-32P]ATP under basal conditions
or after stimulation with 10–4 mol/L
isoproterenol to stimulate ßARs or 10 mmol/L sodium
fluoride (NaF) to activate all G proteins. cAMP was
quantified as described previously.28
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Results |
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Assessment of Hemodynamic Parameters and Cardiac Mass
The SHHF rats were significantly hypertensive relative to the SD control rats as early as 3 months of age (mean arterial pressure, 193.3±4.0 and 111.3±4.6 mm Hg, for SHHF and SD rats, respectively; mean±SEM; n=4 per strain). As shown in Figure 1
, mean arterial,
systolic, and diastolic pressures remained stable
and elevated in SHHF rats until 20 months of age when mean and
systolic pressures fell significantly. Body weights were
significantly greater in SD control rats at all ages; although SD rat
and SHHF rat body weights increased between 3 and 7 months, body weight
did not change in the SD or SHHF rats between 7 and 20 months (SD:
562±13.92 versus 575±14.45 g; SHHF: 435±8.42 versus
437.5±2.5 g, 20 months versus 7 months). LV mass was increased as
early as 3 months in the SHHF rats and increased more with age (Figure 2), reflecting hypertension-induced
cardiac hypertrophy and suggesting that these animals
become hypertensive much earlier than 3 months. As shown in Figure 3A, the maximum rate of contraction [(+)
dP/dT] is significantly depressed at 20 months, and this is preceded
by a reduced lusitropy [(–) dP/dT]. Relative to age-matched SD rats,
LVEDP was elevated in SHHF rats at 3 months (14.2±2.8 versus
5.9±4.0 mm Hg, mean±SEM, n=4/group) and progressively increased
with age (Figure 3B). Cardiac responsiveness to infused
isoproterenol was diminished in 20-month-old SHHF rats as demonstrated
by a significantly depressed chronotropic response (Figure 4). Isoproterenol decreased blood
pressure by 35.2±1.99 mm Hg in all SHHF rats with no difference
among the 4 age groups.
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P<0.05; ANOVA and Bonferroni test).
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Myocardial ßAR Signaling Properties
Biochemical and molecular biological approaches were used to
determine whether abnormalities in ßAR signaling contributed to the
depressed cardiac function in older SHHF rats and to examine the
chronology of any noted changes in ßAR signaling relative to the
observed onset of cardiac dysfunction in this genetic model of heart
failure. ßAR density for control SD rats was 34.6±3.4 fmol/mg
protein and was unchanged with age. ßAR density progressively
declined in SHHF rats, and at 20 months of age was significantly
attenuated (Figure 5). ßAR affinity was
unchanged with age or between control and SHHF rat groups.
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We assessed AC activity to examine the signaling properties of the
ßARs in control versus SHHF rats. Basal AC was not different between
SD and SHHF rats (data not shown), and there was no difference with age
or between control SD (137.3±17.3 pmol ·
mg–1 · min–1,
n=16) and SHHF (133.1±18.1 pmol ·
mg–1 · min–1,
n=16) rats for NaF-stimulated AC activity. However,
isoproterenol-stimulated AC activity was significantly depressed at 14
(24%) and 20 (36%) months in the SHHF rats (Figure 6). Therefore, SHHF rats concomitantly
exhibit age-dependent decreased ßAR density and ßAR-mediated
signaling.
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Expression and Activity of ßARK1
ß-adrenergic receptor kinase (ßARK1 or G protein–coupled
receptor kinase 2 [GRK2]) is a prototypical member of a family of at
least 6 serine/threonine kinases known as the GRKs that specifically
phosphorylate agonist-occupied G protein–coupled receptors
leading to desensitization.12 13 28 ßARK1 is a critical
in vivo modulator of ßAR-mediated myocardial function.28
Human HF is associated with alterations in ßAR signaling, including
downregulation and desensitization of ßARs.6 7 8 9 10 11 12 13 To test
the hypothesis that ßARK1 is involved in the decreased ßAR number
(Figure 5
) and depressed signaling (Figure 6) in SHHF
rats, expression and activity of the myocardial GRKs ßARK1 and GRK5
were examined. Similar to what we have observed before, neither ßARK1
expression nor activity changed with age in the control
rats.31 However, in the SHHF rats, ßARK1 expression
progressively increased with age and was significantly greater than
that in control rats at both 14 (63±10%, n=4, P=0.0008)
and 20 (40±14%, n=4, P=0.0289) months (Figure 7A).
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Enzymatic activity of soluble ßARK1 on the G protein–coupled
receptor substrate rhodopsin (see "Methods") was measured in
cytosolic extracts. ßARK1 activity was significantly increased in
SHHF rats by 14 months (95±36%, n=4, P=0.038; Figure 7B). Unlike ßARK1, there were no changes with age or between
control and SHHF rat groups in membrane-bound GRK5 expression (data not
shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is well established that in human heart failure compromised cardiac function is associated with alterations in the ß-adrenergic signaling cascade including reduced myocardial ßAR density, increased ßARK1, and decreased AC activity.6 7 8 9 10 11 12 13 18 19 20 The purpose of the present study was to characterize in vivo cardiac adrenergic responsiveness with increasing age in a unique genetic model of spontaneous hypertension-induced myocardial hypertrophy and HF (the SHHF/Mcc-facp rat) and to examine components of the ßAR signaling cascade in the same animals. SHHF rats were studied at 3, 7, 14, and 20 months. Relative to age-matched SD control rats, SHHF rats had significantly elevated blood pressure, elevated LVEDP, and LVH as early as 3 months of age. Compared with age-matched SD rats, resting blood pressure was elevated in all SHHF rat groups; compared with 6-month-old SHHF rats, systolic and mean arterial pressures were significantly decreased in 20-month-old SHHF rats. This was coincident with depressed cardiac contractility [(+) dP/dT] and was preceded by depressed lusitropy [(–) dP/dT]. Cardiac sensitivity to isoproterenol was significantly attenuated in 20-month-old SHHF rats. This was coincident with reduced ßAR density and was preceded by elevated ßARK levels and activity. Reduced AC activity at 14 and 20 months was consistent with elevated ßARK at these ages.
The onset of overt HF in the SHHF rats varies with the phenotype of the rat, ranging from 10 to 13 months (obese males) to approximately 24 months in lean females.21 The lean males used in this study reportedly exhibit symptoms of overt HF at 14 to 18 months.21 Documented symptoms and biochemical changes that occur in SHHF rats and that parallel human HF include dyspnea, cyanosis, orthopnea, subcutaneous edema, ascites, hepatomegaly and congestion, pleural effusion, lethargy, piloerection, increased urinary excretion, cachexia, weight loss, reversal of contractile proteins (myosin and actin) to fetal forms, elevated atrial natriuretic peptide, elevated plasma renin activity, elevated circulating norepinephrine, and reduced enzymes involved in fatty acid oxidation.21 22 23 24 25 26 27 We monitored our animals closely via daily visual examination. The 20-month-old lean males used in this study were included on the basis of their exhibition of initial overt symptoms of HF, specifically increased respiratory rate and effort. It was somewhat surprising that they did not exhibit overt HF until 20 months of age, but it is possible this study was performed on homozygote animals because they tend to live longer than the lean males that are heterozygote for the corpulent gene.32
The fundamental molecular mechanisms that contribute to progression in humans from compensatory hypertension-induced cardiac hypertrophy to cardiac dysfunction are poorly understood, but it has been proposed that altered ßAR signaling plays a role.1 Consistent with data from left ventricular samples of patients with HF,6 7 8 9 the present study demonstrates that SHHF rats with compromised cardiac function have reduced ßAR density. Importantly, the in vivo functional changes and the reduction in ßARs observed in the SHHF rats are preceded by an increase in the level and activity of ßARK1. Given that the 20-month-old SHHF rats had just begun to show overt symptoms of HF, elevation of ßARK1 preceded symptomatic HF by at least 6 months. Thus, these data suggest that alterations in ßARK1 may represent a key trigger to the initiation of HF and support the hypothesis that ßARK1 is a good target for development of a therapeutic agent for treatment of HF.33
The present study is the first to examine the in vivo myocardial response of SHHF rats to direct ß-adrenergic stimulation, and it is the first to document definitive changes in components of the ß-adrenergic system in the intact myocardium of this model. Gomez et al24 reported that myocytes isolated from 17- to 18-month-old lean male SHHF rats in overt HF and from hypertrophic hearts of hypertensive Dahl salt-sensitive rats had diminished sarcoplasmic reticulum calcium release in response to electrical depolarization. Interestingly, ßAR stimulation via isoproterenol overcame this deficit in the myocytes from Dahl salt-sensitive rats but produced virtually no response in the myocytes from the animals in HF, perhaps, the authors speculate, because of downregulation of the cardiac ßARs. The data presented herein from 20-month-old lean males demonstrating initial symptoms of overt HF support their conclusion. Consistent with our results in intact myocardium, SHHF myocytes from 6-month-old obese female animals retain their full complement of ßARs relative to myocytes from 4-month-old SD rats.25 However, reduced isoproterenol-stimulated cAMP production by the cells suggested a decrease in AC activity by 6 months of age.25 Exciting preliminary data from our laboratories confirm that, compared with age-matched SD rats, basal cAMP production and isoproterenol-stimulated cAMP production are significantly attenuated in myocytes isolated from 20-month-old lean males and demonstrate that this can be reversed to near normal by adenoviral-mediated expression of a ßARK inhibitor, the ßARKct, a peptide encoding the carboxy-terminus of ßARK1.28 34
To summarize, lean male SHHF rats at the initial stages of overt HF have reduced chronotropic response to ß-adrenergic stimulation. This in vivo manifestation of cardiac dysfunction is coincident with reduced ßAR density and, importantly, preceded by elevated ßARK1 levels and activity. Thus, the data are concordant with the hypothesis that elevated ßARK1 may be an important precipitating factor in the transition from hypertension-induced compensatory hypertrophy to HF. Furthermore, these results provide additional data that strengthen the relevance of the SHHF rat model to the study of human HF.
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Footnotes |
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Drs Anderson and Eckhart were equal contributors to this work.
Received September 18, 1998; first decision October 15, 1998; accepted November 4, 1998.
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 P. Penela, C. Murga, C. Ribas, A. S. Tutor, S. Peregrin, and F. Mayor Jr. Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease Cardiovasc Res, January 1, 2006; 69(1): 46 - 56. [Abstract] [Full Text] [PDF]
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 G. Iaccarino, E. Barbato, E. Cipolletta, V. De Amicis, K. B. Margulies, D. Leosco, B. Trimarco, and W. J. Koch Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure Eur. Heart J., September 1, 2005; 26(17): 1752 - 1758. [Abstract] [Full Text] [PDF]
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 X. Wang, E. Sentex, H. K. Saini, D. Chapman, and N. S. Dhalla Upregulation of {beta}-adrenergic receptors in heart failure due to volume overload Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H151 - H159. [Abstract] [Full Text] [PDF]
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 S. M. Emani, A. S. Shah, M. K. Bowman, D. C. White, S. Emani, D. D. Glower, and W. J. Koch Right ventricular targeted gene transfer of a {beta}-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 787 - 793. [Abstract] [Full Text] [PDF]
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 J. G. Dobson, J. Fray, J. L. Leonard, and R. E. Pratt Molecular mechanisms of reduced {beta}-adrenergic signaling in the aged heart as revealed by genomic profiling Physiol Genomics, October 17, 2003; 15(2): 142 - 147. [Abstract] [Full Text] [PDF]
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 R.-P. Xiao, S.-J. Zhang, K. Chakir, P. Avdonin, W. Zhu, R. A. Bond, C. W. Balke, E. G. Lakatta, and H. Cheng Enhanced Gi Signaling Selectively Negates {beta}2-Adrenergic Receptor (AR)- but Not {beta}1-AR-Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts Circulation, September 30, 2003; 108(13): 1633 - 1639. [Abstract] [Full Text] [PDF]
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 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]
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R. Kacimi and A. M. Gerdes Alterations in G Protein and MAP Kinase Signaling Pathways During Cardiac Remodeling in Hypertension and Heart Failure Hypertension, April 1, 2003; 41(4): 968 - 977. [Abstract] [Full Text] [PDF]
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 I. Tabbi-Anneni, C. Helies-Toussaint, D. Morin, A. Bescond-Jacquet, A. Lucien, and A. Grynberg Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover? J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1003 - 1009. [Abstract] [Full Text] [PDF]
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 N. Spyrou, S. D. Rosen, F. Fath-Ordoubadi, R. Jagathesan, R. Foale, J. S. Kooner, and P. G. Camici Myocardial beta-adrenoceptor densityone month after acute myocardial infarctionpredicts left ventricular volumes at six months J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1216 - 1224. [Abstract] [Full Text] [PDF]
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X. P. Yi, A. M. Gerdes, and F. Li Myocyte Redistribution of GRK2 and GRK5 in Hypertensive, Heart-Failure-Prone Rats Hypertension, June 1, 2002; 39(6): 1058 - 1063. [Abstract] [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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 B Swynghedauw and D Charlemagne What is wrong with positive inotropic drugs? Lessons from basic science and clinical trials Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D43 - D49. [Abstract] [PDF]
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 K. Leineweber, I. Heinroth-Hoffmann, K. Ponicke, G. Abraham, B. Osten, and O.-E. Brodde Cardiac {beta}-Adrenoceptor Desensitization Due to Increased {beta}-Adrenoceptor Kinase Activity in Chronic Uremia J. Am. Soc. Nephrol., January 1, 2002; 13(1): 117 - 124. [Abstract] [Full Text] [PDF]
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L. E. Vinge, E. Oie, Y. Andersson, H. K. Grogaard, G. O. Andersen, and H. Attramadal Myocardial distribution and regulation of GRK and beta -arrestin isoforms in congestive heart failure in rats Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2490 - H2499. [Abstract] [Full Text] [PDF]
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 S. M. Emani, A. S. Shah, D. C. White, D. D. Glower, and W. J. Koch Right ventricular gene therapy with a {beta}-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding Ann. Thorac. Surg., November 1, 2001; 72(5): 1657 - 1661. [Abstract] [Full Text] [PDF]
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G. Iaccarino, J. R. Keys, A. Rapacciuolo, K. F. Shotwell, R. J. Lefkowitz, H. A. Rockman, and W. J. Koch Regulation of myocardial {beta}ARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing {alpha}1B-adrenergic receptors J. Am. Coll. Cardiol., August 1, 2001; 38(2): 534 - 540. [Abstract] [Full Text] [PDF]
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G. Iaccarino, E. Barbato, E. Cipolleta, A. Esposito, A. Fiorillo, W. J. Koch, and B. Trimarco Cardiac {beta}ARK1 Upregulation Induced by Chronic Salt Deprivation in Rats Hypertension, August 1, 2001; 38(2): 255 - 260. [Abstract] [Full Text] [PDF]
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 C.-E. Laurent, R. Cardinal, G. Rousseau, M. Vermeulen, C. Bouchard, M. Wilkinson, J. A. Armour, and M. Bouvier Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R355 - R364. [Abstract] [Full Text] [PDF]
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K. Nagata, C. Communal, C. C. Lim, M. Jain, T. M. Suter, F. R. Eberli, N. Satoh, W. S. Colucci, C. S. Apstein, and R. Liao Altered beta -adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2502 - H2508. [Abstract] [Full Text] [PDF]
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 D. C. White, J. A. Hata, A. S. Shah, D. D. Glower, R. J. Lefkowitz, and W. J. Koch Preservation of myocardial beta -adrenergic receptor signaling delays the development of heart failure after myocardial infarction PNAS, May 9, 2000; 97(10): 5428 - 5433. [Abstract] [Full Text] [PDF]
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M. Dodic, C. Samuel, K. Moritz, E. M. Wintour, J. Morgan, L. Grigg, and J. Wong Impaired Cardiac Functional Reserve and Left Ventricular Hypertrophy in Adult Sheep After Prenatal Dexamethasone Exposure Circ. Res., September 28, 2001; 89(7): 623 - 629. [Abstract] [Full Text] [PDF]
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