(Circulation. 2000;102:1840.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Myocyte Response to ß-Adrenergic Stimulation Is Preserved in the Noninfarcted Myocardium of Globally Dysfunctional Rat Hearts After Myocardial Infarction
Presented in part at the 47th Annual Scientific Sessions of the American College of Cardiology, Atlanta, Ga, March 29 to April 1, 1998, and 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8 to 11, 1998.
From the Department of Medicine and Division of Cardiology, University of Minnesota and VA Medical Center, Minneapolis, Minn.
Correspondence to Inder S. Anand, MD, DPhil (Oxon), VA Medical Center 111-C, Minneapolis MN 55417. E-mail anand001{at}tc.umn.edu
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Abstract |
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Background—Cellular mechanisms underlying the diminished inotropic response of remodeled hearts after myocardial infarction (MI) remain unclear.
Methods and Results—Left ventricular (LV) remodeling and function were assessed by 2D echocardiography and isolated perfused heart studies in 6-week post-MI and sham-operated rats. LV myocytes from sham and noninfarcted MI hearts were used for morphometric and functional studies. ß-Adrenergic receptor (ß-AR) agonist isoproterenol (ISO)-induced contractile response was measured in isolated hearts. The effects of ISO and forskolin on contractile function and calcium transients of isolated myocytes were recorded. ISO-induced cAMP generation was compared in sham and MI myocytes. ß-AR density was measured by radioligand binding. MI hearts were remodeled (LV diameter 8.5±0.3 versus 5.7±0.3 mm, P<0.001) and showed global (% fractional shortening 19.1±2.5 versus 55.3±2.2, P<0.01) and regional contractile dysfunction of noninfarcted myocardium (% systolic posterior wall thickening 37±4 versus 62±10, P<0.01). Isolated heart function (LV developed pressure 58±2 versus 72±3 mm Hg, P=0.004) and ISO concentration response were reduced in MI hearts. Myocytes from the noninfarcted LV were structurally remodeled (32% longer and 18% wider), but their contractile response and intracellular calcium kinetics to ISO and forskolin were not diminished. ß-AR receptor density (Bmax 24±1.5 versus 22.4±1.6 fmol/mg protein) and ß-AR agonist–stimulated cAMP were similar in both groups.
Conclusions—Isolated myocytes from the remodeled and dysfunctional myocardium are structurally modified but contract normally under basal conditions and in response to ß-AR stimulation. ß-AR density is preserved in remodeled myocytes. Nonmyocyte factors may be more important in the genesis of contractile dysfunction in the remodeled rat heart up to 6 weeks after MI.
Key Words: myocardial infarction • myocytes • receptors, adrenergic, beta
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Introduction |
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After a large myocardial infarction (MI), the heart undergoes a series of structural and functional changes known as ventricular remodeling.1 2 The cellular and molecular changes contributing to the global and regional contractile dysfunction of the remodeled myocardium are poorly understood. Of particular intrigue is the lack of strong evidence confirming the presence of contractile abnormalities of individual myocytes from the remote remodeled myocardium. The prevalent hypothesis is that contractile dysfunction is either caused by or at least contributed to by contractile dysfunction of the underlying cardiomyocytes. Abnormalities may involve intrinsic as well as modulated function of these myocytes.3
The ß-adrenergic (ß-AR) system is the predominant neurohormonal modulator of cardiac contractility and may be of greater significance in states of diminished contractile reserve. Since the original description of ß-AR desensitization in the failing human myocardium,4 various abnormalities of its signal transduction pathway have been shown in different models of heart failure. These changes may not be present uniformly, across different species, and in different models of cardiomyopathy.5 Studies of altered ß-AR transduction in the post-MI model have been few, and their findings are contradictory.6 7
In the rat infarct model, we had previously shown normal intrinsic myocyte contractile function.8 The current study was designed to evaluate whether abnormalities of ß-AR–modulated function were present in ventricular myocytes from the remodeled myocardium and if these could be explained by alterations in the ß-AR quantity and agonist-induced cAMP activity. Our findings suggest the presence of a unique state in the evolution of post-MI heart failure, exhibited by marked global and regional contractile dysfunction despite the presence of intact contractility at the myocyte level.
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Methods |
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Experimental Infarction
Myocardial infarction was produced in male Sprague-Dawley rats (weight 150 to 200 g) by ligation of the left coronary artery as previously described.8 In sham-operated rats (sham), the ligature was passed around the coronary artery but not tied. Surviving animals (sham, 35; MI, 50) were studied in 3 groups, 6 weeks later. The experimental protocol was approved by our institutional review board.
Echocardiography
Echocardiography (2D) was performed in all
animals 1 and 5 weeks after surgery2 with a 7.5-MHz,
phased-array transducer (SONOS 2500 Hewlett Packard). M-mode
measurements of cavity size and anterior and posterior left
ventricular (LV) wall thickness in systole and
diastole were made (AWTs or d and PWTs or d). Global LV
function was assessed by calculating LV percent fractional shortening.
The percent posterior wall thickening in systole (%
PWT=[PWTs-PWTd]/PWTdx100) and relative wall thickness
(RWT=2xPWTd/LV internal dimension [ID]d) were
calculated.2
Isolated Heart Function
Isolated heart function was studied in 6 MI and 5 sham group 1
rats. After pentobarbital anesthesia (50 mg/kg
intraperitoneal), hearts were removed and perfused
in a modified "work-performing mode."9 Hearts were
paced at 5.5 Hz, and left atrial (LA), LV, and aortic pressures were
monitored simultaneously. LA inflow and aortic outflow were
measured by electromagnetic flow probes (T206, Transonic Systems).
Baseline LV systolic, diastolic, and
end-diastolic pressures (LVEDP) and peak LV dP/dt maximum
and minimum were recorded (LA inflow 10 mL ·
g-1 ·
min-1; aortic pressure
50 mm Hg). To investigate the Frank-Starling relation, LA inflow
was increased in increments of 2 mL ·
g-1 ·
min-1 to 20 mL ·
g-1 ·
min-1. Response to ß-AR
stimulation was studied with the nonselective agonist isoproterenol
(ISO, 10-10 to
3x10-7 mol/L). ISO was
infused into the LA cannula, and hemodynamics were
measured after a 3-minute stabilization at each concentration. Hearts
were removed and fixed for measurement of infarct size.
Infarct Size Determination
Isolated hearts used for perfusion studies (group 1) were fixed
in 10% phosphate buffered formaldehyde for 24 hours. Hearts were
sectioned (2-mm thickness) from apex to base, and 5-µm
representative sections were prepared from the basal
surface of each slice for Masson’s trichrome staining. Images of
serial sections were captured on a digital camera, and planimetric
measurements were performed with a computerized imaging program
(MetaMorph, Universal Imaging). Infarct size was calculated from 3
mid-wall sections of each heart by the formula [(infarct
endocardial+epicardial circumference)/(LV endocardial+epicardial
circumferences)]x100 and averaged.
Isolated Myocyte Studies
Myocyte Isolation
Ventricular myocytes were isolated from 15 sham and
25 MI hearts (group 2) by retrograde enzymatic perfusion.8
In MI hearts, the infarcted area and a 2-mm rim of peri-infarct tissue
were carefully removed and discarded. Myocytes were isolated from the
remaining noninfarcted myocardium. Myocyte viability
(trypan blue exclusion) of sham (75±4%) and MI cells (70±4%) were
similar. Cells were suspended in a HEPES buffer containing 200
µmol/L extracellular calcium
([Ca2+]o) and divided
into aliquots for functional and morphometric studies.
Myocyte Morphometry
Myocyte dimensions were measured in 100 randomly chosen LV
myocytes by phase-contrast microscopy8 (sham, 1500 cells;
MI, 2500 cells).
Measurement of Myocyte Contractile and Intracellular Calcium
Response
Myocytes loaded with a fluorescent dye Fura-2 AM (Fura-2
acetoxymethyl ester) were randomly selected, and
simultaneous measurements of contraction and intracellular
calcium ([Ca2+]i) were
made with a video edge detector and a high-speed camera coupled to a
dual-excitation fluorescence system.8 Myocytes
were perfused with HEPES buffer (2 mL/min, 30°C) and stimulated at
0.5 Hz. After recording basal function at 1 mmol/L
[Ca2+]o, myocytes were
exposed to either ISO
(10-9,
3x10-9, and
10-8 mol/L) or the
adenylate cyclase agonist forskolin (FSK,
10-7,
10-6, and
10-5 mol/L) for 5 minutes
before recording the effect.
Radioligand Binding
Membrane fractions were prepared from myocytes from the
noninfarcted myocardium of 13 MI and 9 sham
hearts.10 Briefly, membranes were extracted in 0.5 mol/L
KCl and stored at - 70°C.125Iodocyanopindolol (CYP) (New England Nuclear; 5 to 320
pmol/L) was used to label membrane ß-AR. The assay was performed with
50 µg of membrane protein at 37°C for 60 minutes. The
nonselective ß-AR agonist l-isoproterenol (5
µmol/L) was used to calculate nonspecific binding. Competitive
binding curves were derived by means of a selective ß-AR
antagonist, ICI-118 551
(3x10-9 to
3x10-4). Data were
analyzed with Graphpad Prism v 2.0.
cAMP Assay
Agonist-stimulated cAMP generation was measured in myocytes from
6 MI and 6 sham hearts by radioimmunoassay (Amersham
Corp).11
Statistical Analysis
All data are expressed as mean±SEM. Comparison between 2 groups
was made by a 2-tailed Student’s t test. Repeated
variables were analyzed by a repeated-measures ANOVA.
Between-group (sham versus MI) differences in repeated variables
were considered significant if the interaction term P value
was <0.05. This was followed by a post hoc analysis to
identify pairwise differences at each point, only if the interaction
term P value was <0.05. Statistical analysis was
performed by a software package (SPSS 7.5, SPSS Inc). For all tests, a
P value of 
0.05 was considered significant.
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Results |
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Body Weight, Heart Weight, and Infarct Size
MI rats weighed less than sham rats (372±16 versus 428±13 g, P=0.01). The heart weight (1.92±0.07 versus 1.54±0.06, sham) and heart weight (g)–to–body weight (g) ratio (5.49±0.29 versus 3.7±0.2, sham) were significantly increased in MI rats (both P<0.001). Mean infarct size was 38.9±2.4%.
Echocardiography
Results of echocardiography, done on all 35
sham and 50 MI rats, are shown in Table 1
. LV dimensions in systole and
diastole were significantly increased in MI hearts. Most of
the increase was seen 1 week after MI, with only a minimal change
thereafter. LV fractional shortening was reduced by half 1 week after
MI, with no further progression at 5 weeks. Diastolic
posterior wall thickness (PWTd) was similar in MI and sham hearts
throughout the study. However, the systolic posterior wall
thickness (PWTs) decreased in 5-week post-MI hearts, resulting in a
significant reduction in percent systolic thickening of the
posterior wall. Relative posterior wall thickness was reduced in MI
hearts at both 1 and 5 weeks.
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Isolated Work-Performing Heart Function
Infarcted hearts had significantly lower LV developed pressure and
peak positive dP/dt and higher LVEDP at similar LA inflow (10 mL
· g-1 ·
min-1) and aortic
resistance (50 mm Hg; Table 2). The
Frank-Starling relations showed a preload-dependent increase in LV
dP/dt in both groups that was significantly blunted in infarcted hearts
(Figure 1). ISO caused an increase in
peak LV dP/dtmax and
dP/dtmin that was significantly reduced in MI
hearts (Figure 2).
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Isolated Myocyte Structure and Function
Myocyte Morphometry
Myocytes from MI hearts were significantly longer (148±5 versus
112±2 µm versus 109±8, P<0.01) and wider (24±1
versus 20±1 µm, P<0.001) than sham hearts. Similar
changes were noted in myocytes used for functional study (143±4 versus
119±2 µm; P<0.001).
Myocyte Contractile Response
Effect of ISO on myocyte contractility and
[Ca2+]i was studied in 81
MI and 80 sham myocytes (Table 3). In the
basal state ([Ca2+]o
1 mmol/L, 0.2 Hz, 30°C), there was no difference in percent
myocyte shortening between sham and MI myocytes. However, MI myocytes
had a significantly greater mean velocity of shortening and shorter
time to 70% relengthening. ISO caused a significant
concentration-dependent increase in percent myocyte shortening and mean
velocity of shortening and a decrease in time to 70% relengthening in
both groups that was greater in MI as compared with sham myocytes
(P<0.05, interaction term; ANOVA).
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Myocyte Intracellular Calcium Kinetics
At 1 mmol/L
[Ca2+]o, MI myocytes had
a significantly lower resting
[Ca2+]i and greater
[Ca2+]i transient
amplitude. There was no difference in the mean velocity of
[Ca2+]i rise and time to
70% decline in [Ca2+]i
transient between the groups. No difference was seen in the basal
calcium sensitivity (change in length/change in Fura-2 ratio) between
sham and MI cells. ISO caused a concentration-dependent increase in
resting [Ca2+]i,
amplitude of [Ca2+]i,
mean velocity of rise in
[Ca2+]i, and a reduction
in the time to 70% decline in
[Ca2+]i in both groups.
ISO also caused a similar increase in the calcium sensitivity in both
groups. The ISO concentration-dependent increase in amplitude of
[Ca2+]i and mean velocity
of [Ca2+]i rise were
greater in MI as compared with sham myocytes. However, there was no
difference in the response of resting
[Ca2+]i, time to 70%
decline in [Ca2+]i, and
calcium sensitivity ratio between the groups.
Myocyte contractile and
[Ca2+]i response to FSK
were studied in 34 sham and 65 MI myocytes. Like ISO, FSK also caused a
concentration-dependent increase in percent myocyte shortening and
Fura-2 amplitude (Figure 3). These
responses tended to be greater in MI as compared with sham
myocytes.
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ß-AR Studies
Linear plots of bound/free versus bound (Figure 4 insert) demonstrated a saturable,
highly specific binding to a single class of sites. There was no
difference in the equilibrium dissociation constant
(KD) of ß-AR radioligand
binding between MI and sham myocytes (MI, 18.7±5.2 versus sham,
20.6±4.6 nmol/L). The maximal number of radioligand
binding sites was similar in the two groups
(Bmax, MI, 24±1.5 versus sham, 22.4±1.6 fmol/mg
protein).
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The proportion of ß1-AR and ß2-AR was determined by plotting competitive binding curves with CYP and the highly selective ß1-AR antagonist ICI 118551. Binding data indicated that a 2-site model was the perfect fit for ICI 118551. There was no difference in ß1:ß2 AR subtype ratio in myocytes from sham (ß1:ß2 68±2.6%: 32±3.4%) and MI hearts (ß1:ß2 64±3.9%: 36±2.2%). The Ki for ß1- and ß2-AR were 1.24±0.1 and 269±18 nmol/L for sham and 1.56±0.08 and 281.6±20 nmol/L for MI. None of these differences were statistically significant.
cAMP Assay
l-Isoproterenol caused a similar
concentration-dependent increased cAMP production in both
groups of myocytes (Figure 5, P=0.9, ANOVA interaction term).
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Discussion |
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In this study we have shown that the inotropic response to the ß-AR stimulation was reduced in 6-week post-MI hearts but not in ventricular myocytes isolated from their remodeled myocardium. Interestingly, the contractile function and [Ca2+]i kinetics were, in fact, slightly increased in the remodeled myocytes. We also found no differences in the total ß-AR density, ß1:ß2 AR ratio, or agonist-induced cAMP generation in myocytes isolated from the noninfarcted myocardium.
Ventricular Remodeling in Rat Infarct Model
Serial echocardiography confirmed the presence
of LV remodeling and contractile dysfunction. Marked enlargement of LV
cavity was evident by 1 week, accompanied by reduction in global LV
function (percent fractional shortening). By 5 weeks, although there
was only a minimal further increase in LV dimension, the remote
myocardium developed contractile dysfunction with reduction
in percent systolic thickening of the posterior wall. Global LV
systolic and diastolic dysfunction was also
confirmed in isolated heart function studies. The blunted
Frank-Starling relation seen in infarcted rat hearts is similar to that
reported in humans and supports the observation that contractile
reserve, albeit diminished, is still preserved in failing
myocardium.
An important finding in this model is that compensatory hypertrophy of the remote noninfarcted myocardium does not increase wall thickness.2 12 The PWTd at 5 weeks did not differ between sham and MI hearts. This "inadequate hypertrophy" of the surviving myocardium could contribute to the global and regional contractile dysfunction by worsening wall stress.
Myocyte Function in Remodeled Myocardium
It is reasonable to suspect that intrinsic contractile
abnormalities of surviving myocytes may contribute to contractile
dysfunction seen in the noninfarcted myocardium.
Significant structural remodeling was indeed noted in myocytes isolated
from these regions, similar to those described by us
previously.8 However, these remodeled myocytes did not
show any abnormalities of contractile function or
[Ca2+]i kinetics in the
basal state. Whether abnormalities of myocyte contractile function
develop in the noninfarcted myocardium remains
controversial. Studies on myocytes specifically isolated from the
remote regions have found no evidence of contractile
dysfunction,8 13 14 in contrast to others where a clear
distinction between the remote and peri-infarct regions was not
made.15 16 It is important to emphasize that in post-MI
remodeling, myocyte hypertrophy can be differentially
regulated across peri-infarct and remote
myocardium.14 17 This distinction may be
useful in interpreting results of myocyte function in other comparable
studies reporting conflicting results.
The decrease in global inotropic response to ß-AR stimulation in isolated infarcted hearts observed in our study is comparable to previous studies in the rat model.6 18 Myocyte loss as a result of MI and consequent ventricular dilation and increased wall stress could explain some of the diminished contractile response in isolated heart preparations. This, however, cannot explain the attenuated contractile response to ISO reported in noninfarcted isolated papillary muscle.19 20 A major limitation of multicellular preparations is that significant changes occur in the extracellular matrix in this model that may alter mechanical properties of the noninfarcted myocardium and affect its contractile response.21 22 Litwin and Morgan19 studied papillary muscles of 6-week post-MI rats and found that ISO caused a concentration-dependent increase in [Ca2+]i similar to that seen in our isolated myocytes. However, unlike the preserved inotropic response in the latter, agonist-induced increase in papillary muscle tension was significantly blunted. A blunted mechanical response in the presence of a normal [Ca2+]i in papillary muscle could be explained by a defect in mechanical coupling of myocytes resulting from extracellular matrix abnormalities.
Contractile response to ß-AR stimulation has been reported to be diminished in myocytes from other models of heart failure.23 24 25 26 It is important to note that in these studies, even basal myocyte contractile function was significantly depressed. Moreover, these studies only tested a single concentration of ISO, making direct comparisons difficult. The finding of normal or exaggerated inotropic response in our myocytes is not unique among published literature. Recently, McIntosh et al27 found that ventricular myocytes isolated from the subendocardial region in a rabbit model of post-MI heart failure had shorter action potentials and greater [Ca2+]i amplitudes. These findings were in stark contrast to the cells from the subepicardial region that demonstrated blunted peak [Ca2+]i and longer action potentials.
ß-AR Modulation in Postinfarction Remodeling
Since ß-AR downregulation may be dependent on the cause of heart
failure,5 variations in receptor modulation in post-MI
heart failure could aid in understanding the beneficial mechanisms of
clinical ß-AR blockade. In the rat infarct model, myocardial ß-AR
have been found to be preserved,10 28 29 30 31
downregulated,7 or even upregulated.18 Unlike
Sethi et al,7 who found that ß-AR downregulation
correlated well with the extent of hemodynamic
dysfunction, we could not confirm these findings despite profound
global and regional contractile dysfunction in our rats. It is unclear
whether they studied only the remote noninfarcted
myocardium. The differences reported in the literature may
be explained on whether the remote or entire LV was studied. Recent
studies30 32 show that ß-AR density is preserved in the
remote noninfarcted myocardium of 5-week post-MI hearts,
whereas significant reduction is seen in the peri-infarct
zone.30 These data further support the emerging hypothesis
that surviving ventricular myocytes may be differentially
regulated after a large MI.17 33 The apparently preserved
and indeed mildly enhanced modulated function in myocytes from the
remodeled myocardium is further strengthened by our finding
of normal agonist-induced cAMP generation. These findings are
internally consistent with the results of our functional
studies with the adenylate cyclase agonist FSK. Whereas
investigation of the ß-AR transduction pathway distal to cAMP is
beyond the scope of the present study, it is possible that
abnormalities involving the G proteins and cAMP-independent mechanisms
could explain the diminished modulated function in failing hearts.
Limitations
Although our studies were limited to an early stage of post-MI
heart failure, it is possible that myocyte contractile dysfunction and
abnormalities of ß-AR signal transduction appear later in the natural
history of this model. Another significant limitation common to all
isolated myocyte studies is that cells studied may not be
representative of the myocytes in the intact remodeled
myocardium. The isolation procedure could
inadvertently affect the yield of viable but
dysfunctional myocytes. Despite this possibility, the finding of
supranormal function in a significant proportion of myocytes is in
itself interesting.
Conclusions
The rat infarct model appears to have significant differences from
other models of heart failure. In this model, LV chamber dilation and
global LV dysfunction occur early after MI (1 week), with a gradual
development of regional contractile dysfunction in the remote
noninfarcted myocardium. Myocytes from the remote
noninfarcted regions of LV myocardium are structurally
remodeled similar to that seen in other models of dilated
cardiomyopathy. However, unlike other models, both
basal and modulated functions of ventricular myocytes
remain preserved for up to 6 weeks after MI. Contractile response to
nonselective ß-AR agonist may even be increased in these
ventricular myocytes. These results demonstrate that early
in the course of global myocardial dysfunction, unitary contractile
machinery could still be functionally intact. In addition, ß-AR
density, ß1:ß2 subtype
ratio, and agonist-induced cAMP production are also preserved
in these myocytes. Nonmyocyte factors such as increased wall
stress and extracellular matrix abnormalities probably make significant
contributions to global and regional contractile dysfunction in this
model. ß-AR downregulation may not always be present in remodeled
ventricular myocardium despite the presence of
an attenuated global adrenergic inotropic response.
Received March 6, 2000; revision received May 12, 2000; accepted May 15, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161–1172.
2.
Litwin SE, Katz SE, Morgan JP, et al.
Serial echocardiographic assessment of left
ventricular geometry and function after large myocardial
infarction in the rat. Circulation. 1994;89:345–354.
3. Bristow MR. Why does the myocardium fail? Insights from basic science. Lancet. 1998;352(suppl 1):SI8-SI14.
4. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205–211.[Abstract]
5. Bristow MR, Feldman AM. Changes in the receptor-G protein-adenylyl cyclase system in heart failure from various types of heart muscle disease. Basic Res Cardiol. 1992;87:15–35.
6. Clozel JP, Holck M, Osterrieder W, et al. Effects of chronic myocardial infarction on responsiveness to isoprenaline and the state of myocardial beta adrenoceptors in rats. Cardiovasc Res. 1987;21:688–695.[Medline] [Order article via Infotrieve]
7.
Sethi R, Dhalla KS, Beamish RE, et al. Differential
changes in left and right ventricular adenylyl cyclase
activities in congestive heart failure. Am J Physiol. 1997;272:H884–H893.
8.
Anand IS, Liu D, Chugh SS, et al. Isolated myocyte
contractile function is normal in postinfarct remodeled rat heart with
systolic dysfunction. Circulation. 1997;96:3974–3984.
9.
Grupp IL, Subramaniam A, Hewett TE, et al. Comparison
of normal, hypodynamic, and hyperdynamic mouse hearts using isolated
work-performing heart preparations. Am J Physiol. 1993;265:H1401–H1410.
10. Chasteney EA, Liang CS, Hood WB Jr. Beta-adrenoceptor and adenylate cyclase function in the infarct model of rat heart failure. Proc Soc Exp Biol Med. 1992;200:90–94.[Medline] [Order article via Infotrieve]
11.
Steinberg SF, Robinson RB, Lieberman HB, et al.
Thrombin modulates phosphoinositide
metabolism, cytosolic calcium and impulse initiation in the
heart. Circ Res. 1991;68:1216–1229.
12. Roberts CS, Maclean D, Braunwald E, et al. Topographic changes in the left ventricle after experimentally induced myocardial infarction in the rat. Am J Cardiol. 1983;51:872–876.[Medline] [Order article via Infotrieve]
13.
Lefroy DC, Crake T, Del Monte F, et al.
Angiotensin II and contraction of isolated myocytes from
human, guinea pig, and infarcted rat hearts. Am J
Physiol. 1996;270:H2060–H2069.
14.
Melillo G, Lima JA, Judd RM, et al. Intrinsic myocyte
dysfunction and tyrosine kinase pathway activation underlie the
impaired wall thickening of adjacent regions during postinfarct left
ventricular remodeling. Circulation. 1996;93:1447–1458.
15.
Cheung JY, Musch TI, Misawa H, et al. Impaired cardiac
function in rats with healed myocardial infarction: cellular vs
myocardial mechanisms. Am J Physiol. 1994;266:C29–C36.
16.
Capasso J, Anversa P. Mechanical performance of
spared myocytes after myocardial infarction in rats: effects of
captopril treatment. Am J Physiol. 1992;263:H841–H849.
17. Kramer CM, Rogers WJ, Park CS, et al. Regional myocyte hypertrophy parallels regional myocardial dysfunction during post-infarct remodeling. J Mol Cell Cardiol. 1998;30:1773–1778.[Medline] [Order article via Infotrieve]
18. van Veldhuisen DJ, Brodde OE, van Gilst WH, et al. Relation between myocardial beta-adrenoceptor density and hemodynamic and neurohumoral changes in a rat model of chronic myocardial infarction: effects of ibopamine and captopril. Cardiovasc Res. 1995;30:386–393.[Medline] [Order article via Infotrieve]
19.
Litwin SE, Morgan JP. Captopril enhances intracellular
calcium handling and beta-adrenergic responsiveness of
myocardium from rats with postinfarction failure.
Circ Res. 1992;71:797–807.
20. Qi X, Rouleau JL. Beta-adrenergic responsiveness of papillary muscles in the rat postinfarction model. Can J Physiol Pharmacol. 1996;74:1166–1170.[Medline] [Order article via Infotrieve]
21.
Litwin SE, Litwin CM, Raya TE, et al.
Contractility and stiffness of noninfarcted
myocardium after coronary ligation in rats: effects
of chronic angiotensin converting enzyme inhibition.
Circulation. 1991;83:1028–1037.
22. Weber KT, Sun Y, Tyagi SC, et al. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol. 1994;26:279–292.[Medline] [Order article via Infotrieve]
23. Harding SE, Jones SM, O’Gara P, et al. Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response. J Mol Cell Cardiol. 1992;24:549–564.[Medline] [Order article via Infotrieve]
24.
Zhang XQ, Moore RL, Tillotson DL, et al. Calcium
currents in postinfarction rat cardiac myocytes. Am J
Physiol. 1995;269:C1464–C1473.
25.
Yamamoto S, Tsutsui H, Tagawa H, et al. Role of myocyte
nitric oxide in beta-adrenergic hyporesponsiveness in heart failure.
Circulation. 1997;95:1111–1114.
26. McMahon WS, Mukherjee R, Gillette PC, et al. Right and left ventricular geometry and myocyte contractile processes with dilated cardiomyopathy: myocyte growth and beta-adrenergic responsiveness. Cardiovasc Res. 1996;31:314–323.[Medline] [Order article via Infotrieve]
27.
McIntosh MA, Cobbe SM, Smith GL.
Heterogeneous changes in action potential and intracellular
Ca2+ in left ventricular myocyte sub-types from rabbits
with heart failure. Cardiovasc Res. 2000;45:397–409.
28. Yamamoto J, Ohyanagi M, Morita M, et al. 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]
29.
Cherng WJ, Liang CS, Hood WB Jr. Effects of metoprolol
on left ventricular function in rats with myocardial
infarction. Am J Physiol. 1994;266:H787–H794.
30. 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]
31.
Huang B, Wang S, Qin D, et al. Diminished basal
phosphorylation level of phospholamban in the
postinfarction remodeled rat ventricle: role of beta-adrenergic
pathway, Gi protein, phosphodiesterase, and
phosphatases. Circ Res. 1999;85:848–855.
32. Kompa AR, Gu XH, Evans BA, et al. Desensitization of cardiac beta-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat: evidence for the role of Gi but not Gs or phosphorylating proteins. J Mol Cell Cardiol. 1999;31:1185–1201.[Medline] [Order article via Infotrieve]
33. Kramer CM, Nicol PD, Rogers WJ, et al. Reduced sympathetic innervation underlies adjacent noninfarcted region dysfunction during left ventricular remodeling. J Am Coll Cardiol. 1997;30:1079–1085.[Abstract]
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