(Hypertension. 2000;36:42.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Increase in Gi
Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy
From Klinik III (I.K., O.Z., B.C., M.B.) and Klinik II (F.J.) für Innere Medizin, Universität zu Köln, Germany; and Cardiovascular Research, Hoechst Marion Roussel (G.I., W.L.), Frankfurt am Main, Germany.
Correspondence to Prof Dr Michael Böhm, Klinik III für Innere Medizin Universität zu Köln, Joseph-Stelzmann-Str 9, 50924 Köln, Germany. E-mail michael.boehm{at}medizin.uni-koeln.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in ß-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to ß-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical Gs
protein and ß-adrenoceptor density were not significantly altered by
MI in both strains. However, immunochemical Gi was
increased (1.5-fold) in the noninfarcted left ventricle of the SHR in
which infarction had been induced when compared with that in SHR that
underwent sham operation. This increase was observed especially in rats
with a high plasma ANP level. Furthermore, there was a positive
correlation between Gi and the extent of post-MI
remodeling in WKY. A similar correlation between Gi and
the extent of hypertensive hypertrophy was observed in SHR.
In conclusion, the vulnerability of hypertrophied hearts to
ischemic damage is greater than that of normotensive hearts. An
increase in Gi could be one mechanism involved in the
transition from cardiac hypertrophy to cardiac failure when
chronic pressure overload and loss of contractile mass from
ischemic heart disease coexist.
Key Words: myocardial infarction • cardiomegaly • ventricular remodeling • G proteins • atrial natriuretic factor
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ventricular remodeling after myocardial infarction (MI) is increasingly recognized as being one of the most important causes of chronic heart failure.1 To define the pathophysiological mechanisms underlying that process, coronary artery ligation in the rat model has been well studied.2 3 This classic model is attractive because the structural and functional alterations that occur during post-MI remodeling (eg, hypertrophy of noninfarcted myocardium, an increase in collagen content, and progressive contractile dysfunction) are similar to those alterations observed in humans.3 However, in addition to ischemic damage, chronic stress that is due to residual coronary stenosis and, in particular, systemic hypertension, is often involved in the progression of human ischemic cardiomyopathy. The coronary artery ligation model in which there are no additional pathologic factors such as those cited may not be applicable to clinical settings.
Hypertensive cardiac hypertrophy is another major cause of
heart failure.4 Although hypertrophy is
thought of initially as being a compensatory mechanism, chronic
pressure overload results in the decompensation of the hypertrophied
heart.5 In addition, left ventricular (LV)
hypertrophy is an independent risk factor for
MI.4 Thus, the prevalence of hypertensive patients
suffering MI is increasing, and their prognosis is worse than that of
normotensive patients with MI. However, there is no precise report
regarding the mechanisms underlying post-MI remodeling that occurs in
cases of pre-existing hypertrophy. Although the mechanisms
responsible for the transition from cardiac hypertrophy to
cardiac failure are redundant and possibly dependent on the type of
damage to the myocardium, an activation of the sympathetic
nervous system with myocardial release of norepinephrine
and consequent desensitization of the myocardial ß-adrenergic signal
transduction have been generally demonstrated in chronic heart
failure,6 hypertensive cardiac
hypertrophy,7 and post-MI
remodeling.8 9 ß-Adrenergic desensitization produces an
important contribution to contractile dysfunction in these conditions.
An increase of inhibitory G protein subunit
(Gi)10 11 and a downregulation of
ß-adrenergic receptors11 12 are the key alterations that
have been identified to date. In this study, the spontaneously
hypertensive rat (SHR), which is the widely used experimental model in
the study of hypertensive hypertrophy,13 was
used to simulate post-MI remodeling with hypertensive
hypertrophy, and the alteration in the ß-adrenergic
receptor G-protein regulated system was investigated.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Postinfarction Remodeling Model
All experiments were performed in accordance with the German animal protection law. Male Wistar-Kyoto rats (WKY) and SHR (age 16 weeks) (Harlan Winkelmann, Indianapolis, Ind) were anesthetized with an intraperitoneal injection of ketamine (35 mg/kg) plus xylazine (2 mg/kg) and were mechanically ventilated. The pericardium was opened via left thoracotomy, and the left coronary artery was ligated 2 to 3 mm beneath its origin. The sham operation consisted of the identical procedure except for coronary ligation. Ten weeks after the surgery, the rats were reanesthetized, and the right carotid artery was cannulated with a polyethylene catheter to enable the monitoring of blood pressure and heart rate. Then each heart was excised and was mounted on a Langendorff apparatus. Each isolated heart was perfused in the working-heart mode with a filling pressure of 15 mm Hg and an afterload pressure of 60 mm Hg, as described previously.14 After the evaluation of cardiac performance, the heart was weighed, and the LV was sectioned transversely into 4 slices. Photographs were taken from each slice, and the tissues were then snap-frozen in liquid nitrogen and were stored at -80°C. The area of scarring and the LV were determined by planimetry and were corrected for the tissue weight.
Myocardial Membrane Preparation
Noninfarcted LV myocardium from rats with infarcted
hearts and the corresponding portion from the hearts of rats that
underwent sham operation were homogenized by means of a
glass Teflon homogenizer in
homogenization buffer (5 mmol/L Tris/HCl,
1 mmol/L EDTA, 5 mmol/L MgCl2, 5 mg/L
leupeptin, and 5 mg/L aprotinin, pH 7.4). The homogenate
was centrifuged at 500g for 10 minutes. The
supernatant was incubated with an addition of 1 mol/L KCl for 10
minutes and was centrifuged at 100 000g for 30
minutes. The final pellet was resuspended in incubation buffer (25
mmol/L Tris/HCl and 20 mmol/L MgCl2, pH 7.4)
and was stored at -80°C. All preparation was performed at 4°C.
Protein concentrations were determined according to the method of
Bradford.15
Radioligand Binding Study
Assays were performed in a total volume of 250 µL of
incubation buffer. The incubation was performed at 37°C for 60
minutes. ß-Adrenoceptors in myocardial membranes were studied with
125I-cyanopindolol, as described
previously.11
Western Blot Analysis
G protein subunits were studied with
immunoblotting techniques.11 The
polyclonal antiserum MB1 was raised in rabbits against the
carboxyl-terminal decapeptide of retinal transduction (KENLKDCGLF)
coupled to keyhole limpet hemocyanine. The MB1 recognized
Gi1 and Gi2 but not
Go and
Gi3.12 The membrane fractions
were electrophoresed in SDS-polyacrylamide gels and were
transferred to nitrocellulose filters. The filters were incubated with
the first antibodies for Gi (MB1) or
Gs (RM/1) and then with the second antibody
(horseradish peroxidase–conjugated goat anti-rabbit IgG, Amersham).
Immunoreactive signals were detected by means of the ECL kit
(Amersham).
Plasma ANP Determination
Plasma ANP was measured with a specific radioimmunoassay kit
according to the manufacturer’s instruction (Biotrend) after
extraction by means of Sep-Pak C18 cartridges (Bond Elut,
Varian).
Northern Blot Analysis of Cardiac ANP
Total RNA was isolated from LV tissue and was analyzed
as described previously.16 In brief, 10 µg of total RNA
was separated by gel electrophoresis, was blotted onto nylon filters,
and was fixed by ultraviolet crosslinking. The blots were hybridized
with a random-primed 32P-radiolabeled cDNA probe
for ANP. The signals on the autoradiographs were quantified
densitometrically. GAPDH was used as an internal control to normalize
for differences in loading of RNA.
Isolated Papillary Muscle Studies
In separate experiments, animals from SHR groups were assigned
to papillary muscle studies, and isometric force of contraction was
recorded as described previously.17 Ten weeks after
the coronary ligation or sham operation, the hearts were
excised, and LV noninfarcted papillary muscles were dissected free. The
muscles were suspended in an organ bath and were electrically
stimulated (frequency 1 Hz, impulse duration 5 ms, voltage 10% to 20%
above threshold). After the baseline data had been recorded, the
muscles were incubated with 30 nmol/L isoproterenol.
Statistical Analysis
All data are described as mean±SEM. Statistical significance
was estimated with the Student t test for unpaired
observations or 1-way ANOVA with Fisher’s least significant difference
as the post hoc test. The slopes for linear regression lines were
compared by ANCOVA. A value of P<0.05 was considered
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Structural and Functional Alterations
The rat hearts in which MI had been induced were characterized by ventricular hypertrophy in the noninfarcted area and marked thinning of the infarcted LV free wall. Infarct size, hemodynamics, and heart weights are summarized in the Table. In the both strains, LV and right ventricular (RV) weights normalized to body weight were increased, and LV pressure and peak positive dP/dt were decreased by MI. Most of these alterations were well related to the infarct size (Figure 1). The slopes of linear regression for RV weight and LV(+) dP/dt were significantly (P<0.01) steeper in SHR than in WKY (Figure 1B, C).
|
|
Plasma and Cardiac ANP
Significant increases in plasma ANP concentration (Figure 2A) that were due to MI were seen in SHR
(P<0.001) and WKY (P<0.05). Sham-operated
(P<0.001) or infarcted (P<0.001) SHR had a
higher plasma ANP level than did respective WKY. ANP mRNA levels in the
remodeled LV myocardium (Figure 2B) were upregulated
in SHR (P<0.05) but not in WKY (P=0.144).
|
P<0.001 vs
respective WKY.
ß-Adrenergic Receptors
There were no differences in ß-adrenergic receptor density of LV
membranes between WKY and SHR (125I-cyanopindolol
bound in fmol/mg protein n=8 to 11 each, WKY-sham 27±2, WKY-MI 24±4,
SHR-sham 26±5, SHR-MI 31±6). No significant change during post-MI
remodeling was detected in either strain. The antagonist
affinities as judged on the basis of the kDa values did not differ
among all groups (62 to 88 pmol/L).
Immunochemical Gs and Gi
The RM/1 recognized both 45- and 52-kD forms of
Gs. Immunochemical signals of the both
Gs bands were similar between sham-operated
and MI animals in either WKY and SHR (45-/52-kDa in densitometric unit
n=8 to 11 each, WKY-sham 50±5/41±7, WKY-MI 49±5/52±4, SHR-sham
48±4/53±6, SHR-MI 47±4/52±6). On the other hand, immunochemical
Gi was increased by 53% (P<0.01)
in SHR-MI compared with that in SHR-sham, but it was not altered in WKY
(Figure 3).
|
Contraction of Isolated Papillary Muscle
The basal force of contraction of papillary muscles isolated from
SHR was significantly decreased (P<0.05) in SHR-MI
(0.58±0.12 mN) when compared with that in SHR-sham (0.71±0.35 mN). As
shown in Figure 4, the
isoproterenol-stimulated force of contraction was more markedly
depressed (P<0.01) in SHR-MI (0.66±0.12 mN, 118±8% of
basal value) than in SHR-sham (1.10±0.51 mN, 150±6% of basal
value).
|
Remodeling and Gi
Figure 5A shows a significant
correlation between Gi and infarct size in WKY
but not in SHR. The same data of Gi were then
analyzed in a classification according to plasma ANP level; low
ANP, <100 pg/m; high ANP, >100 pg/mL (Figure 5B). Although
there was no difference in infarct size among the 3 MI groups (WKY-low
ANP 21±2%, SHR-low ANP 22±3%, SHR-high ANP 24±4%), there was a
significant increase in Gi of SHR-high ANP
compared with that in SHR-low ANP (P<0.01) and WKY-low ANP
(P<0.001) groups. Finally, the relationship of LV weight to
Gi was analyzed in rats that had
undergone sham operation (Figure 6A) and
in those in which post-MI remodeling occurred (Figure 6B). The
significant linear correlation was observed in the SHR that had
undergone sham operation and in WKY with post-MI remodeling.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This is the first report to explore the ß-adrenergic receptor G-protein alterations in the post-MI remodeling model of SHR. It demonstrated that hypertensive hypertrophied hearts underwent more progressive LV dysfunction because of MI compared to normotensive hearts, that Gi
increased in the post-MI
remodeling myocardium with pre-existing
hypertrophy in association with the impairment of
contractile response to ß-adrenergic stimulation, and that both the
development of LV hypertrophy that occurred because of
chronic pressure overload and that resulting from the loss of
myocardium were correlated with an enhancement of
Gi. The pathophysiological alterations after coronary artery ligation in rats resemble those in patients with MI.1 3 Although the infarcted myocardium thins with a scar formation, the noninfarcted myocardium hypertrophies in response to the increased wall stress. Pfeffer et al2 have demonstrated that there is a good correlation between the degree of impairment of LV function and infarct size in the rat model of infarction. Two previous studies compare hypertensive and normotensive hearts with respect to functional changes after MI. Fletcher et al18 have shown that the reductions of LV pressure and peak stroke volume that developed because of post-MI remodeling were more remarkable in SHR than in normotensive rats. Nishikimi et al19 have indicated that the increases in LV end-diastolic pressure and RV weight after MI were greater in SHR than in WKY. Similarly, in this study, the increase in RV weight and LV dysfunction in proportion to infarct size were more prominent in SHR than in WKY. RV weight reflecting the elevated LV filling pressure is a good marker for cardiac decompensation.2 19 In addition, plasma ANP and cardiac ANP mRNA levels, which are reliable indices of decompensation after infarction,20 increased more remarkably in SHR than in WKY. These mechanical and neurohumoral changes indicate that hypertrophied hearts are more susceptible to ischemic damage and demonstrate more advanced heart failure than do normotensive hearts.
The SHR is an established model of genetic hypertension in which
hypertensive cardiac hypertrophy similar to that occurring
in hypertensive patients develops.13 The hypertrophied
myocardium is initially an adaptational response to reduce
wall stress, but that hypertrophy progresses to heart
failure.5 The prolonged sympathetic activation leading to
ß-adrenergic desensitization is a key alteration in the transition
from cardiac hypertrophy to cardiac failure.7
In human end-stage heart failure, a downregulation of ß-adrenoceptors
and an increase in Gi have been well
documented.10 11 12 Nevertheless, there are controversial
reports concerning the number (a decrease,7 no
change,21 or an increase22 ) of
ß-adrenoceptors in the heart of SHR. The majority of previous
reports7 23 24 have demonstrated an increase in the
Gi of SHR, with the exception of 1 report
showing no change.25 In this study, neither the numbers of
ß-adrenoceptor nor Gi were significantly
different in WKY-sham and SHR-sham. The inconsistent result
might be explained by several factors that could influence the advance
of ß-adrenergic desensitization. Because cardiac
hypertrophy advances with age, the difference in the age of
SHR could explain the inconsistency. In addition, a genetic
heterogeneity among SHR provided by different suppliers
could evoke a variability in the development of
hypertension.13 The extent of cardiac
hypertrophy and cardiac failure may vary, even when the
rats are of similar age, in different rat
colonies.5 13
The infarcted area was completely replaced by fibrous tissue and no
longer contributed to LV performance at 10 weeks after MI.
Therefore, the alterations in the ß-adrenergic receptor G protein
signaling that was associated with impaired LV function were studied in
the residual noninfarcted myocardium. No significant change
in ß-adrenoceptor number was induced by MI in WKY; this is
consistent with prior studies examining the noninfarcted
myocardium of rats with chronic MI.9 26 Recent
reports27 28 have demonstrated that
Gi increased 4 to 16 weeks after MI in the
failing heart of normotensive rats. As shown in this study (Figure 5A), an increase in Gi correlates with
infarct size in normotensive hearts. Drexler et al20
demonstrated that plasma ANP increased in association with the
decompensation of post-MI normotensive rat hearts only when the infarct
size exceeded 30% of LV. Thus, the smaller infarct size in our model
could account for the less alteration in Gi
and the less overt heart failure in WKY with MI when compared with the
respective results in previous studies27 28 in which rats
with a large MI (>30% of LV) were enrolled. In contrast, a
significant increase in Gi that was
independent of infarct size, and was in accord with a high level of
plasma ANP, was induced by MI in hypertensive rat hearts. In addition,
papillary muscles isolated in the post-MI remodeled heart of SHR had a
reduced contractile response to ß-adrenergic stimulation. Because
ß-adrenoceptors and Gs were unchanged, these
findings suggest that the activation of Gi is
functionally important for the impairment of LV function in this animal
model. It is noteworthy that there is a close correlation between the
level of Gi and LV hypertrophy
either as a result of chronic hypertension (in SHR) or of post-MI
remodeling (in WKY), which could suggest that
Gi signals the hypertrophic responses and/or
stimuli, even though the causal relation remains to be elucidated.
There is a considerable variability in Gi and
LV hypertrophy in SHR-sham that could account for the
variable level of Gi and the heart failure
that developed after similarly sized MI in SHR. In this respect, an
elevation of Gi preceding MI should predict a
poor outcome of post-MI remodeling in hypertensive hearts. Considered
together, an increase in Gi could be involved
in the transition from cardiac hypertrophy to cardiac
failure in response to pressure overload and a coexisting loss of
contractile mass that results from infarction.
Although it is not thoroughly understood which mechanisms are
responsible for the regulation of Gi
expression, it has been speculated that the mechanisms should involve
chronic activation of the sympathetic nervous system. Chronic exposure
of ß-adrenoceptor agonists has been reported to increase
Gi in rat hearts.29 Our results
indicating good correlation between Gi and 2
different phenotypes of LV hypertrophy encourage
this hypothesis, because a magnitude of LV hypertrophy
should reflect the time-integrated exposure to either pressure overload
or ischemic damage, both of which should be accompanied by
prolonged sympathetic activation.7 8 Recent
studies30 31 have revealed that
ß2-adrenoceptor couples dually with
Gs and Gi, that
ß1-adrenoceptor couples exclusively with
Gs, and that the coupling of
ß2-adrenoceptor to Gi
negates Gs-mediated cardiac
contractility. ß2-Adrenoceptor
signaling and its coupling to Gi could be
relevant to the pathogenesis of cardiac hypertrophy and
failure.
|
Acknowledgments |
|---|
This work was supported by the Deutsche Forschungsgemeinschaft (M.B.) and NOVARTIS Foundation (Japan) for the Promotion of Science (I.K.).
Received November 11, 1999; first decision December 1, 1999; accepted February 2, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161–1172.
2.
Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ,
Spadaro J, Kloner RA, Braunwald E. Myocardial infarct size and
ventricular function in rats. Circ Res. 1979;44:503–512.
3. Goldman S, Raya TE. Rat infarct model of myocardial infarction and heart failure. J Card Fail. 1995;1:169–177.[Medline] [Order article via Infotrieve]
4. Stokes J, Kannel WB, Wolf PA, D’Agostino RB, Cupples LA. Blood pressure as a risk factor for cardiovascular disease: the Framingham Study: 30 years of follow-up. Hypertension. 1989;13(suppl I):I13–I18.
5. Boluyt MO, Bing OH, Lakatta EG. The aging spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. Eur Heart J. 1995;16(suppl N):19–30.
6. Cohn JN. The sympathetic nervous system in heart failure. J Cardiovasc Pharmacol. 1989;14(suppl 5):S57–S61.
7.
Böhm M, Castellano M, Paul M, Erdmann E. Cardiac
norepinephrine, beta-adrenoceptors, and
Gi-proteins in prehypertensive and
hypertensive spontaneously hypertensive rats. J Cardiovasc
Pharmacol. 1994;23:980–987.[Medline]
[Order article via Infotrieve]
8.
Vantrimpont P, Rouleau JL, Ciampi A, Harel F, de
Champlain J, Bichet D, Moye LA, Pfeffer M. Two-year time course and
significance of neurohumoral activation in the Survival and
Ventricular Enlargement (SAVE) Study. Eur Heart
J. 1998;19:1552–1563.
9. Yamamoto J, Ohyanagi M, Morita M, Iwasaki T. Beta-adrenoceptor-G protein-adenylate cyclase complex in rat hearts with ischemic heart failure produced by coronary artery ligation. J Mol Cell Cardiol. 1994;26:617–626.[Medline] [Order article via Infotrieve]
10. Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Van Dop C. Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest. 1988;82:189–197.
11.
Böhm M, Gierschik P, Jakobs KH, Pieske B,
Schnabel P, Ungerer M, Erdmann E. Increase of
Gi in human hearts with dilated but not
ischemic cardiomyopathy.
Circulation. 1990;82:1249–1265.
12.
Böhm M, Eschenhagen T, Gierschik P, Larisch K,
Lensche H, Mende U, Schmitz W, Schnabel P, Scholz H, Steinfath M,
Erdmann E. Radioimmunochemical quantification of
Gi in right and left ventricles from patients
with ischaemic and dilated cardiomyopathy and
predominant left ventricular failure. J Mol Cell
Cardiol. 1994;26:133–149.[Medline]
[Order article via Infotrieve]
13.
Trippodo NC, Frohlich ED. Similarities of genetic
(spontaneous) hypertension: man and rat. Circ Res. 1981;48:309–319.
14.
Linz W, Wohlfart P, Schölkens BA, Becker RHA,
Malinski T, Wiemer G. Late treatment with ramipril increases survival
in old spontaneously hypertensive rats. Hypertension. 1999;34:291–295.
15. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.[Medline] [Order article via Infotrieve]
16.
Böhm M, Zolk O, Flesch M, Schiffer F, Schnabel P,
Stasch JP, Knorr A. Effects of angiotensin II type 1
receptor blockade and angiotensin-converting enzyme
inhibition on cardiac ß-adrenergic signal transduction.
Hypertension. 1998;31:747–754.
17. Cremers B, Flesch M, Südkamp M, Böhm M. Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil. J Cardiovasc Pharmacol. 1997;29:692–696.[Medline] [Order article via Infotrieve]
18. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Effects of hypertension on cardiac performance in rats with myocardial infarction. Am J Cardiol. 1982;50:488–496.[Medline] [Order article via Infotrieve]
19. Nishikimi T, Yamagishi H, Takeuchi K, Takeda T. An angiotensin II receptor antagonist attenuates left ventricular dilatation after myocardial infarction in the hypertensive rat. Cardiovasc Res. 1995;29:856–861.[Medline] [Order article via Infotrieve]
20.
Drexler H, Hanze J, Finckh M, Lu W, Just H, Lang RE.
Atrial natriuretic peptide in a rat model of cardiac
failure: atrial and ventricular mRNA, atrial content,
plasma levels, and effect of volume loading. Circulation. 1989;79:620–633.
21. Ohsuzu F, Katsushika S, Maie S, Akanuma M, Yanagida S, Sakata N, Ishida H, Aosaki N, Nakamura H. Enhanced myocardial adenylate cyclase activity in spontaneously hypertensive rats. Jpn Circ J. 1992;56:301–309.[Medline] [Order article via Infotrieve]
22.
Atkins FL, Bing OH, DiMauro PG, Conrad CH, Robinson KG,
Brooks WW. Modulation of left and right ventricular
ß-adrenergic receptors from spontaneously hypertensive rats with left
ventricular hypertrophy and failure.
Hypertension. 1995;26:78–82.
23. Marcil J, Thibault C, Anand-Srivastava MB. Enhanced expression of Gi-protein precedes the development of blood pressure in spontaneously hypertensive rats. J Mol Cell Cardiol. 1997;29:1009–1022.[Medline] [Order article via Infotrieve]
24. Anand-Srivastava MB. Enhanced expression of inhibitory guanine nucleotide regulatory protein in spontaneously hypertensive rats: relationship to adenylate cyclase inhibition. Biochem J. 1992;288:79–85.
25. Murakami T, Katada T, Yasuda H. Reduction in the activity of the stimulatory guanine nucleotide-binding protein in the myocardium of spontaneously hypertensive rats. J Mol Cell Cardiol. 1987;19:199–208.[Medline] [Order article via Infotrieve]
26. Gu XH, Kompa AR, Summers RJ. Regulation of beta-adrenoceptors in a rat model of cardiac failure: effect of perindopril. J Cardiovasc Pharmacol. 1998;32:66–74.[Medline] [Order article via Infotrieve]
27.
Peterson DJ, Ju H, Hao J, Panagia M, Chapman DC, Dixon
IMC. Expression of Gi2 and
Gs in myofibroblasts localized to the infarct
scar in heart failure due to myocardial infarction. Cardiovasc
Res. 1999;41:575–585.
28. Sethi R, Elimban V, Chapman D, Dixon IMC, Dhalla NS. Differential alterations in left and right ventricular G-proteins in congestive heart failure due to myocardial infarction. J Mol Cell Cardiol. 1998;30:2153–2163.[Medline] [Order article via Infotrieve]
29.
Müller FU, Boheler KR, Eschenhagen T, Schmitz W,
Scholz H. Isoprenaline stimulates gene transcription of the
inhibitory G protein -subunit
Gi-2 in rat heart. Circ Res. 1993;72:696–700.
30.
Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA,
Müller FU, Eschenhagen T, Lefkowitz J, Koch WJ, Lakatta EG.
Coupling of ß2-adrenoceptor to Gi proteins
and its physiological relevance in murine cardiac
myocytes. Circ Res. 1999;84:43–52.
31.
Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG.
Recent advances in cardiac ß2-adrenergic signal transduction.
Circ Res. 1999;85:1092–1100.
This article has been cited by other articles:
 |
|
 |
|
  G. R. Norton, D. G. A. Veliotes, O. Osadchii, A. J. Woodiwiss, and D. P. Thomas Susceptibility to systolic dysfunction in the myocardium from chronically infarcted spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H372 - H378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Selvetella, E. Hirsch, A. Notte, G. Tarone, and G. Lembo Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence Cardiovasc Res, August 15, 2004; 63(3): 373 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Seeland, I. Kouchi, O. Zolk, F. Jockenhovel, G. Itter, W. Linz, and M. Bohm Effects of diuretic treatment on cardiac and circulating RAS in chronic heart failure post-myocardial infarction in rats Eur J Heart Fail, June 1, 2003; 5(3): 241 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Baumer, C. Schumann, B. Cremers, G. Itter, W. Linz, F. Jockenhovel, and M. Bohm Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide J Appl Physiol, March 1, 2002; 92(3): 1058 - 1063. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||